Apparatus, Method and Computer-Readable Storage Medium For Evaluating A Physiological Condition of a Patient

ABSTRACT

A method is provided that includes receiving measurements of biological elements from a blood sample of a patient. The respective biological elements are managed by the endocrine system, which is organizable in axes including a corticotropic axis, gonadotropic axis, thyreotropic axis and somatotropic axis. The method includes calculating a plurality of indexes as functions of the measurements. The indexes reflect physiological relationships between the biological elements and the hormones that manage the respective biological elements, and at least some of the indexes reflect physiological relationships between hormones across axes of the endocrine system. The method also includes evaluating the indexes by axis of the endocrine system to facilitate identification of one or more dysfunctions capable of participating in the genesis, installation and evolution of a pathology, and thereby formulate a diagnosis of the patient. And the method includes administering a therapy to the patient in accordance with the diagnosis.

FIELD

The present invention generally relates to evaluating a physiologicalcondition of a patient, and more particularly, relates to a biologicalsimulation model for evaluating the physiological condition of thepatient.

CONTENT

The content of the present application as provided below is broken downin the following sections.

1. Summary

2. Background

3. Brief Description of the Drawings

4. Detailed Description

-   -   4-1. The Integrative Biological Simulation Model    -   4-2. Testing the Biological Simulation Model Model on        Pathologies    -   4-3. Testing the Biological Simulation Model on the Endocrine        System    -   4-4. The Endobiogenic Medical Assistant (EMA™)    -   4-5. Conclusions

5. Evaluation Guidelines

6. Claims

7. Abstract

1. SUMMARY

Various example embodiments of the present invention may be summarizedas follows:

A. A methodology is provided, which is based on an integrative approachof physiological mechanisms which support the functioning of the humanbody. It utilizes a Biological Simulation Model for evaluating thephysiological links existing between specific biological elementsmeasured in blood and their hormonal managers.

It permits to one establish the real state of an organism and tohighlight the physiological regular phenomena and their dysfunctions,which participate in the genesis, installation and evolution of thepathology.

An amount of 35 measurements (called indexes) is shown as anillustration, with their rationale and their testing on variouspathologies. Also shown is the functioning of the endocrine systemthrough the Biological Simulation Model.

B. A data system, based on the above methodology, referred to hereinwithout loss of generality as the Endobiogenic Medical Assistant (EMA™),is provided to assist the practitioner both on clinical andphysiological evaluation, with an automated physiological diagnosticassistant (illustrated in this document) highlighting both the maindysfunctions and their required correcting actions. The therapeutic isalso assisted with a menu of recommended treatments on clinicalsymptomatic findings and physiological actions. A “Walkthrough aConsultation” example is included in the document to illustrate how thesystem may operate.

The system also serves as a tracking tool to follow up progress on thepatient state and verify the validity of the diagnostic and theefficiency of the selected therapy.

2. BACKGROUND

Exemplary embodiments of the present invention provide a BiologicalSimulation Model and associated apparatus, method and computer-readablestorage medium for evaluating a patient (“exemplary” as used hereinreferring to “serving as an example, instance or illustration”).

Exemplary embodiments of the present invention consider the organism asa whole, made of elements in permanent interaction and working togetheras a network. It quantifies the physiological relationships at organ andorganism-level that drive the functioning of the body, and it helpsidentify the underlying dysfunctions linked with a disease and theirevolution with or without treatment. It goes beyond the symptomaticapproach of the disease and takes into account the state of the patientin its overall functioning, the so called “terrain” of the patient,which plays a key role in the ability of an individual to face adisease. For example, exemplary embodiments of the present inventionfacilitate an understanding of why an individual faced with a very coldweather will contract pneumonia, while similar cold weather had noeffect on the individual a year earlier. Similarly, for example,exemplary embodiments of the present invention facilitate anunderstanding of why out of ten people faced with very cold weatherunder similar conditions, one will contract sinusitis, two will contractpneumonias, one will contract shingles, the rheumatoid arthritis of onewill flare-up, while the other five will not contract anything.

The disease may be viewed not only as caused by a factor X, but may alsoand primarily be caused by one or more dysfunctions of the organism. Infact, the disease, as may be seen through the symptoms, may beconsidered the end of an internal process where the body hasunsuccessfully attempted to contain the exposure. The symptom may beconsidered the signal that the body has failed in its attempt, and itwill need to mobilize many more resources, unless it gets outside help.The Biological Simulation Model of exemplary embodiments of the presentinvention facilitates an understanding of what happened and identify theroot causes that drove the failure of the organism.

Exemplary embodiments propose an explanation of the basic functioning ofthe organism, under control of the endocrine system, as the manager ofthe physiological phenomena that permits the life maintenance within thebody, through a sequence of catabolic and anabolic metabolic activities.

Regulation of the internal environment requires a single and autonomoussystem manager that has the ability to interact permanently with allorgans and body systems in order to direct and control all input/outputtransfers. This system manager also needs the ability to act for its ownsafeguard in order to remain efficient and manage the organism.

The endocrine system can fulfill the mission of managing the overallorganism. The endocrine system is connected to all systems, and may actanywhere in the body and react to all kinds of solicitations: sensorial,metabolic or physiological. The endocrine system is able to reset thebasal state (homeostasis) and to participate in its evolution; and itparticipates in growth, ensures cells nutrition and prioritizes thedistribution of energetic resources. The endocrine system manages allfactors involved in the defense system of the organism, and manages twofundamental attributes of the organism: short term and long termadaptation, which are hormone-dependent. It also has enough autonomy tocorrect its own deficiencies.

As an example, in the 1930s, Hans Selye described the role of theendocrine system in the body response to specific aggressions such asthird-degree burns, spread-out infections, hemorrhages and the like,which were associated with identical reactions from the organism, whichhe referred to as the General Adaptation Syndrome (GAS).

Exemplary embodiments propose not only a global view on how theendocrine system organizes the body response to any kind of aggression(external or internal, physical, chemical, viral, emotional, etc.), butalso how it manages the maintenance of the basic structure of theorganism.

3. BRIEF DESCRIPTION OF THE DRAWINGS

Having thus described the invention in general terms, reference will nowbe made to the accompanying drawings, which are not necessarily drawn toscale, and wherein:

FIGS. 1-6 are graphs illustrating various data produced according toexamples testing a model according to exemplary embodiments of thepresent invention;

FIG. 7 is a graph of the endocrine system;

FIG. 8 is a graph providing a summary of the catabolic and anabolicactivities of the axes of the endocrine system;

FIG. 9 is a schematic block diagram of an apparatus configured tooperate in accordance with exemplary embodiments of the presentinvention;

FIG. 10 is an overall system flow according to various exemplaryembodiments of the present invention; and

FIGS. 11-35 illustrate portions of various example displays that may bepresented during operation of the system of exemplary embodiments of thepresent invention.

4. DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Likenumbers refer to like elements throughout.

4-1. The Integrative Biological Simulation Model

The Biological Simulation Model of exemplary embodiments of the presentinvention enables measurement of the overall functioning of the organismin its various aspects: endocrine, metabolic and tissular aspects, andenables such measurement at cell, organ and global level, through aseries of measurements, called indexes. Through these indexes, theBiological Simulation Model may facilitate a better understanding of thephysiological functioning of the organism, identifying its pathologicaltendencies, and/or determining of the imbalances that may be the rootcauses of a pathology. The Biological Simulation Model also facilitatestracking the evolution of the organism and the risks for relapses,following the efficiency of treatment, and/or identifying the sideeffects of a medication.

The indexes are calculated from data obtained from a single, inexpensiveblood draw, and many of the indexes are based on only two to threevariables, along physiological relationships identified in publishedresearch work. The simplicity of the selection is an essential factor toensure reliability of the norms and reproducibility across patients,under similar terrain conditions, whether they are pathologic or not.The consistency with a global view of the endocrine system is achievedby defining indexes, which are mostly relative indexes, i.e., indexeswhich are functions of other indexes, which represent over 80% of allindexes.

An index is designed by first defining what is to be evaluated, such asa level of activity (usually relative), a yield, or a circulating rate.Relevant parameters affecting the index are then identified andselected, which parameters will be used as variables in the formulaicrepresentation of the index. These parameters are data obtained from theblood draw, other indexes or some combination of both. Various indexesare in the form of a ratio, and in such instances, the parameters mayappear in the numerator (the index “varies like”) or denominator (theindex “varies like the reverse”) of the ratio, like in the basicformulas of physical science.

If it is desirable to differentiate the weight of two or more parameterson the same level (numerator or denominator), a mathematicaldifferentiator may be introduced, such as a square or cubed function.Additionally, a digit number may be added, such as to maintain the indexin the same band than other similar indexes. One of the objectives inthe design of the indexes is to capture the relevant parameters and toselect a set of formulas fully consistent with each other.

It should be noted that the indexes are designed bottom-up, born fromproved physiological relationships and tested through clinicalevaluation. For this reason, as well as the complexity of the humanorganism, there is no global index, because it would not satisfy thecriteria of reliability and reproducibility.

Exemplary embodiments of the present invention also provide an apparatusand computer-readable storage medium that may assist a user in theirdiagnostic evaluation of a patient and in the selection of anappropriate therapy. Although exemplary embodiments of the presentinvention contemplate a large number of indexes, the following presentexamples of a number of indexes (both direct and indirect).

Blood draw (sample) data (19 data, of which 16 are used by the system):

red cells, leucocytes and their distribution (neutrophils throughmonocytes)

haemoglobin and platelets count

LDH (Lactate dehydrogenase), CPK (creatine phosphokinase) and TSH(thyroid stimulating hormone)

osteocalcin, alkaline phosphatases and their isoenzymes (hepatic, bone,intestine)

potassium and calcium

EXAMPLES OF INDEXES

1. The genital ratio measures the relative tissular activity ofandrogens versus estrogens, and is defined as follows: Genital Ratio=Redcells/(Leukocytes×10³).

Red cells synthesis is primarily caused by androgens, which arestimulated by the luteinizing hormone (LH) from the anterior pituitary.Leucocytes, on the other hand, are under the influence of estrogens,which are stimulated by the follicle-stimulating hormone (FSH). Thus,the ratio of red cell to white cell counts (Red cells/White cells) isreferred to as the genital ratio and is equal to the ratio of LH/FSH.The 10³ factor is required to adjust both the numerator and thedenominator to the same units, such as when the red cells are expressedin millions units/mm³, and white cells are expressed in thousandsunits/mm³.

** Publications:

a. Androgens—Red cells:

M. Alen, Androgenic Steroid Effects on Liver and Red Cells, BJ SportsMedicine, vol. 19(1), pp 15-20, March 1985.

N Hara et al., Decline of the Red Blood Cells Count in PatientsReceiving Androgen Deprivation Therapy for Localized Prostate Cancer,Division of Urology, Dept of Regenerative and Transplant Medicine,Niigata University, Niigata, Japan, Urology, vol. 75, issue 6, pp.1441-45, June 2010.

b. Estrogens—Leukocytes:

R. C. Crafts M. D., Effects of Estrogens on the Bone Marrow of AdultFemale Dogs, Dept of Anatomy, Boston University School of Medicine,Boston, Mass., USA, American Society of Haematology, Blood 1948 vol. 3,pp 276-285.

Y Zheng et al., Immuno-Histochemical Characterization of theEstrogens-Stimulated Leucocytes Influx in the Immature Rat Uterus, Deptof Obstetrics and Gynecology, Division of Reproductive Biology, TheUniversity of Pennsylvania Medical School, Philadelphia, USA Journal ofLeucocyte Biology, vol. 44, pp 27-32 (1988).

2. The genito-thyroid (GT) index measures the thyroid response to theestrogenic demand, and is defined as follows: Genito-Thyroid RatioIndex=Neutrophils/Lymphocytes, both variables of which may be expressedin percentages. The granulocytes secretion (neutrophils represent 90% ofgranulocytes which include neutrophils, eosinophils and basophils) istypically under the influence of estrogens, while the lymphocytes areunder TSH influence. Thus, the ratio of neutrophils to lymphocytesrepresents the thyroid response to the estrogenic demand, and not thereverse.

The paradox here comes from the TSH which is the upper level stimulationof the thyroid and usually varies like the reverse of the thyroidactivity. If TSH is medium to low, the thyroid is usually strong, andvice versa; if the TSH is medium to high, the thyroid response to theestrogenic demand is usually low.

** Publications:

a. Estrogens—Neutrophils (Granulocytes):

R. C. Crafts M. D., Effects of Estrogens on Number of Neutrophils inBone Marrow of Adult Female Dogs, Dept of Anatomy, Boston universitySchool of Medicine, Boston, Mass. U.S.A., American Society of HematologyBlood vol. 3 N° 3, pp 276-285 (1948).

S. A. Robertson et al., Ovarian Steroid Hormones Regulate GranulocyteMacrophage Colony, Dept of Obstetrics and Gynecology, University ofAdelaide, South Australia, PubMed PUBMI 8838016.

Notably the R. C. Crafts publication is the same as indicated above asNeutrophils are part of the Leucocytes (or White Cells). The summary ofthe publication in fact reads as follows: “Large doses of estrogens havea profound effect on the bone marrow of adult dogs. The initial reactionis a great increase in the number of Neutrophilic elements in the bonemarrow. These neutrophils are released into the blood stream, causing amarked rise in the total white cells count.”

b. Lymphocytes—TSH:

T. Mukuta et al., Activation of T Lymphocyte Subsets by Synthetic TSHReceptor, Dept of Medicine, Wellesley Hospital, University of Toronto,Ontario, Canada, Journal Clinical Endocrinol. Metab. 80 (4), pp. 1264-72(April 1995).

3. The adaptation ratio measures the relative activity of the ACTHhormone in its adaptative function relative to FSH, and is defined asAdaptation Ratio=Eosinophils//Monocytes=ACTH//FSH.

Under stimulation of ACTH, glucocorticoids (cortisol) reduce thecirculating rate of eosinophils through sequestration in the spleen andthe lungs (Thorn test). Conversely, an increase of eosinophils, acharacteristic of a congestion phase, will indicate a shortage ofglucocorticoids, hence an elevation of the upper level stimulatinghormone, the ACTH. The eosinophils will vary like ACTH.

The monocytes are depending on the estrogenic response to a FSHstimulation, and are inhibited by estrogens, hence the lower areestrogens the higher are monocytes and FSH, and the monocytes will varylike FSH.

The initial physiological link of the General Adaptation Syndrome isthus characterized by the link between ACTH and FSH.

By definition, the ratio eosinophils//monocytes will be calledAdaptation Ratio and it will be equal to ACTH//FSH, representing theresponse of FSH to ACTH. Adaptation Ratio represents both the level ofthe aggression and the response of the organism to the aggression: thelower is the adaptation index, the higher is the aggression and usuallythe higher is the glucocorticoid response (cortisol) generating a sharpreduction of eosinophils, consistent with a low adaptation ratio.

** Publications:

N. Sabag et al., Cortisol-Induced Migration of Eosinophils to LymphoidOrgans, Laboratory of Experimental Endocrinology, Department ofExperimental Morphology, University of Chile Medical School, SantiagoNorte, Casilla 21104, Correo 21, Santiago, Chile, Cellular and MolecularLife Sciences, vol. 34, no. 5, pp. 666-67, May 1978.

R. R. de Mowbray et al., ACTH in Diagnosis of Adrenal Insufficiency(THORN Test), Guy's hospital and Chelsea Hospital for Women, U.K.,British Medical Journal, vol. 1 (4800) pp 17-21 (Jan. 1953).

H. Selye, The General Adaptation and the Diseases of Adaptation, Journalof Clinical Endocrinology & Metabolism, vol. 6, no. 2, pp. 117-230(1946).

M. A. Giembycz et al., Pharmacology of the Eosinophils, Imperial CollegeSchool of Medicine at the National Heart and Lung Institute, London,U.K., Pharmacological Reviews, vol. 51, no. 2, pp 213-340.

J. E. Cox & F. H. A. Mohamed, Studies of Pituitary-Adrenal-TestisInteraction in Sheep. II. The Effects of Repeated Injections OfAdrenocorticotrophic Hormone Outside The Breeding Season, Division ofEquine Studies and Farm Animal Surgery Department of Veterinary ClinicalScience University of Liverpool Veterinary Field Station Leahurst,Neston, South Wirral, L64 7TE, U.K., Therionology (1988) April; 29(4):pp. 867-72.

4. The starter index measures the relative activity of glucagon versusadrenaline and is defined as follows: Starter index=Leucocytesmobilization/Platelets mobilization.

Notably, the normal reaction to a stress situation is an adrenalinedischarge via the beta sympathetic. It is the General AdaptationSyndrome which blocks the cell access to energy except in sensitiveareas such as brain and heart, which need extra energy. It is theso-called immediate mobilization which distributes energy where it ismost needed. At the end of the aggression, an insulin discharge willdrive back to the original state (homeostasis).

When the organism is faced with a lasting or chronic aggression, it willchoose the glucagon route via the alpha sympathetic along thestimulation path alpha→CRF→TRH→pancreas→glucagon, with glucose dischargewhich will increase glycemia, generating an increase in metabolism. Itis so called mediate mobilization, which is an anticipation over theGeneral Adaptation Syndrome. In a situation of pathologic aggression,the organism will always choose the glucagon route to increase itsenergy reserves.

The mobilization of the leucocytes out of the splanchnic reserve will betriggered via the alpha sympathetic→glucagon route, while the plateletsmobilization out the splanchnic reserve will be triggered via the betasympathetic→adrenaline route, hence the starter definition to measurethe relative activity of glucagon versus adrenaline.

5. The Cata-Ana index measures the relative part of the catabolicactivity versus the anabolic activity of the organism, and representsthe mobilization of factors participating in the set up of the immediatedefense system, within the general adaptation syndrome. The Cata-Anaindex is defined as Cata-Ana Index=Genito-thyroid Ratio/GenitalRatio×Starter index.

The genito-thyroid index represents the catabolic response of thethyroid to the anabolic estrogenic demand during the general adaptationsyndrome. The Cata-Ana index varies like the Genito-thyroid ratio.

The Genital ratio tends to decrease in case of an aggression, by themobilization of leucocytes and acts as an amplifying factor, while theStarter, depending whether the response is an adrenaline driven defense(immediate mobilization) or a glucagon driven defense (mediateaggression) will be an amplification factor or a moderating factor. Incase of a pathologic aggression, a higher starter will tend to reducethe cata-ana in relative terms since the glucagon route may assist theglucocorticoide response. The Cata-Ana index will vary like the reverseof the Genital ratio and the Starter index.

The product Genital Ratio×Starter index, is also defined as the AdjustedGenital ratio and it measures the Genital ratio, when excluding theeffect of adaptation.

6. The cortisol index measures the cortisol activity of the adrenalgland and its excretion during the adaptation syndrome, and is definedas follows: Cortisol Index=Cata-Ana Index/Adaptation Ratio.

As indicated above, the Cata-Ana index measures the relative catabolicversus anabolic activity and represents the initial response to anaggression. The cortisol activity will vary like the Cata-Ana index.

As also indicated above, the adaptation ratio equals the ACTH/FSH ratio.ACTH is the stimulating hormone of the cortisol, and hence, ACTH varieslike the reverse of cortisol. That is, the lower the ACTH, the lower theadaptation ratio and the higher the cortisol activity. The Cortisolindex will vary like the reverse of the adaptation ratio

Consequently the cortisol index varies like the Cata-Ana index and likethe reverse of the adaptation ratio.

7. The adrenal gland index measures the activity of the adrenal gland,which has two types of activities, namely, an adaptive activity torespond to the aggression, and a permissive activity to support thearomatization of adrenal androgens into estrogens.

The adrenal gland index is defined as:

Adrenal Gland Index=Cata-Ana Index/Genital Ratio.

In this regard, below are 2 different points to explain how the indexwas built:

The Cata-Ana index measures the mobilization of factors participating inthe set up of the immediate defense system within the general adaptationsyndrome, and hence, adrenal gland activity varies like the Cata-Anaindex.

The lower the genital ratio, the stronger the estrogenic activity andthe higher the permissive demand for additional aromatization from theadrenal gland activity, and hence, the adrenal gland index varies likethe reverse of the genital ratio.

8. The histamine index measures the activity of histamine, an aminosubstance available in most tissues (particularly in lungs and liver),which triggers capillary dilatation and increases secretory activity.The histamine index is defined as follows:

Histamine Index=(Eosinophils×Platelets×Genital Ratio)/Cortisol Index.

In the representation of the histamine index, the cortisol index andeosinophils vary in reverse to one another and tend to amplify histaminewhen cortisol decreases (hence eosinophils increase), and reducehistamine when cortisol increases (hence eosinophils decrease).

Platelets amplify the capillary dilatation (as histamine does) by theirrole on blood coagulation, and hence, histamine varies like platelets.And an increase in the genital ratio reflects a higher solicitation ofandrogens, which may increase histamine, and hence, histamine varieslike the genital ratio.

** Publications:

R. W. Schayer et al., Binding of Histamine in Vitro and its Inhibitionby Cortisone, Rheumatic Fever Research Institute, NorthwesternUniversity, Medical School, Chicago, Ill., USA, Am J Physiology(September 1956) vol. 187, no. 1, pp. 63-65.

A. P. Lima et al., Effects of Castration and Testosterone Replacement onPeritoneal Histamine Concentration and Lung Histamine Concentration inPubertal Male Rats, Depts of Physiology and Morphology, Faculties ofMedicine and Odontology of Ribeirao Preto, University of Sao Paulo,Ribeirao Preto, Sao Paulo, Brazil, Journal of Endocrinology (2000), vol.167, no. 1, pp. 71-75.

9. The adaptogen index measures the type of adaptation used by theorganism, and is defined by the ratio of potassium to calcium, i.e.,Adaptogen Index=K/Ca.

In situations of acute stress, using the general adaptation syndrome,there is a slight increase of Calcium and a limited change in Potassium,in terms of blood content: the adaptogen index will experience a slightreduction, which will not last.

In situations of repetitive stress, on the other hand, the aldosteronewill be solicited and it will trigger a reduction of Potassium, hence adecrease in the adaptogen index (K//Ca ratio).

The adaptation short cut, using beta-endorphins, will not usealdosterone, and will maintain or eventually increase the blood contentof Potassium, while the Calcium blood rate will be reduced byglucocorticoids: as a consequence, the adaptogen index (K//Ca ratio)will increase.

10. The βMSH/αMSH ratio index is defined as follows: βMSH/αMSHIndex=Thyroid Metabolic Index/Adaptogen Index.

Beta-MSH (βMSH) and alpha-MSH (αMSH) are melanocyte-stimulating hormonesproduced in the intermediate lobe of the pituitary gland and are usedfor reactivating the adrenal gland by increasing the number of ACTHreceptors and triggering their sensitivity. They are two complementaryways to stimulate ACTH:

a. The regular cortisol regulation is done through the ACTH-cortisolroute, hence βMSH and an adrenaline discharge triggered by the betasympathetic.

b. While the required surplus in cortisol is obtained through the αMSHroute, e.g., if cortisol activity is insufficient, the αMSH route willbe used in greater proportion to increase the cortisol activity,triggered by the alpha sympathetic.

The βMSH/αMSH index measures the relative level of adaptation responsebetween the normal route (acute stress using βMSH) and the short cutusing αMSH, hence the use of the adaptogen index in the formula.

The formula of this index (thyroidian index//adaptogen index) is a wayto assess the relative strength of the beta sympathetic versus the alphasympathetic:

-   -   1. The thyreotropic axis of the endocrine system is stimulated        by the beta sympathetic, hence the βMSH/αMSH index varies like        the metabolic activity of the thyroid (thyroid metabolic index).    -   2. βMSH/αMSH index increases in regular stress (with an increase        of aldosterone and decrease of potassium, i.e., a decrease in        the adaptogen index), while it decreases in the adaption short        cut, as indicated above (with an increase of potassium and        decrease of calcium, i.e., an increase of the adaptogen index),        hence the βMSH/αMSH index varies like the reverse of the        adaptogen index.

11. The metabolic estrogens index measures the metabolic activity ofestrogens, and is defined as follows: Metabolic EstrogensIndex=TSH/Osteocalcin.

TSH stimulates estrogens metabolic activity, and hence, the metabolicestrogens index varies like TSH.

Osteocalcin participates in the osseous anabolism under the stimulationof estrogens. The measured osteocalcin is a blood content, andtherefore, the lower the osteocalcin in blood, the higher itsparticipation in the osseous anabolism, and vice versa, hence themetabolic estrogens index varies like the reverse of osteocalcin.

By extension, the ratio TSH//osteocalcin measures the metabolic activityof estrogen.

** Publications:

a. TSH—Estrogens:

A. De Lean et al., Sensitizing Effect of Treatment with Estrogens on TSHResponse to TRH, Medical Research Group in Molecular Endocrinology,Laval University Hospital Center, Quebec, Canada, AJP: Endocrinology andMetabolism, vol. 233, Issue 3, E235-E239, 1977.

I. M. Spitz et al., The Thyrotropin (TSH) Profile in IsolatedGonadotropin Deficiency: A Model to Evaluate the Effect of Sex Steroidson TSH Secretion, Population Council, New York, N.Y., USA, Dept ofEndocrinology & Metabolism, Shaare Zedek Medical Center and HebrewUniversity, Hadassah Medical School, Jerusalem, Israel, Journal ofClinical endocrinology & Metabolism, vol. 57, N° 2, 415-420.

E. Marquese et al., The effect of Droloxifene and Estrogen on ThyroidFunction in Postmenopausal Women, Department of Medicine, Brigham andWomen's Hospital, Harvard Institute of Medicine, Boston, Mass., USA,Journal of Clinical endocrinology & Metabolism, vol. 85, N° 114407-4410.

D. D. Abech et al., Effects of Estrogen Replacement Therapy on PituitarySize, Prolactin and TSH concentrations in Menopausal Women, Faculdad deMedicina, Universidad de Culaba and Porto Alegre, Brazil, GynecologyEndocrinology, vol. 4, 223-226 (2005).

b. Estrogens—Serum osteocalcin and Osteoblast proliferation:

D. C. Williams et al., Effects of Estrogen and Tamoxifen on SerumOsteocalcin Levels in Ovariectomized Rats, Bone Biology Research Group,Lilly Research Laboratories, Indianapolis, Ind. 46285, USA, Bone Miner:1991 Sep. 14 (3) pp 205-220.

M. Nasu et al., Estrogen Modulates Osteoblast Proliferation and FunctionRegulated by Parathyroid Hormone in Osteoblastic SaOS-2 Cells: Role ofInsulin-Like Growth Factors (IGF)-I and IGF-Binding Protein-5, ThirdDivision, Department of Medicine, Kobe University School of Medicine,7-5-1 Kusonoki-cho, Chuo-ku, Kobe 650, Japan, Journal of Endocrinology(2000) 167, pp 305-313.

12. The metabolic androgens index measures the metabolic activity ofandrogens, and is defined as follows: Metabolic AndrogensIndex=Metabolic Estrogens Index×Adjusted Genital Ratio, as per the abovedefinition of the Adjusted Genital ratio, excluding the impact ofadaptation. This covers the total metabolic activity of androgens atstructure level, i.e., prior to the adaptation impact.

13. The growth index measures the activity of the Growth Hormone (GH)and is defined as follows: Growth index=AP Bone Isoenzymes//Osteocalcin.

Alkaline phosphatases bone isoenzymes represent the anabolism growth, asstimulated by estrogens, which target for 80% the osseous growth and for20% the muscular growth. By extension, it may be assumed thatgrowth-hormone GH activity varies like the bone isoenzymes.

Osteocalcin participates in the osseous anabolism, under the stimulationof estrogens. As previously noted, the measured osteocalcin is a bloodcontent, and accordingly, the lower is the osteocalcin in blood, thehigher is its participation in the osseous anabolism, and vice versa. GHactivity varies like the reverse of osteocalcin

** Publications:

Anna G. Nilsson, Effects of Growth Hormone Replacement Therapy on BoneMarkers and Bone Mineral Density in Growth Hormone-deficient Adults,Department of Medical Sciences, University Hospital, Uppsala, Sweden,Horm Res 2000 (54) pp 52-57.

H. Tobiume et al., Serum Bone Alkaline Phosphatase Isoenzyme Levels inNormal Children and Children with GH Deficiency: A Potential Marker forBone Formation and Response to GH Therapy, Department of Pediatrics,Oyakama University Medical School, Okayama 700, and DiagnosticDevelopment SRL Inc, Tokyo 163-08, Japan, The Journal of ClinicalEndocrinology & Metabolism, vol. 82, N) 7 pp 2056-2061 (1997).

A. R. Baker et al., Osteoblast-Specific Expression of Growth HormoneStimulates Bone Growth in Transgenic Mice, Department of EndocrineResearch, Genentech Inc., South San Francisco, Calif. 94080, USA, MolCell Biol. 1992 December; 12(12) pp 5541-5547.

14. The bone remodeling index measures the level of bone remodeling andthe degree of alteration of bone and bone cartilage, and it is definedas follows: Bone Remodeling Index=TSH×Growth Index.

Bone remodeling varies like the growth index as the growth indexexpresses the metabolic activity of the growth hormone.

Similarly, bone remodeling varies like TSH as the TSH stimulatesestrogens in their contribution of growth activity, primarily towardsosseous growth.

** Publications:

C. Ohisson et al., Growth Hormone and Bone, Research Centre forEndocrinology and Metabolism, Sahlgrenska University Hospital, Goteborg,Sweden, Endocrine Reviews 1998 Feb. 1, vol. 19(1), pp. 55-79.

K. Brixen et al., Growth Hormone (GH) and Adult Bone Remodeling: ThePotential use of GH in Treatment of Osteroporosis, Department ofEndocrinology and Metabolism, Aarhus University Hospital, Denmark, JPediatry Endocrinology 1993 January-March; 6(1) pp 65-71.

15. The thyroid metabolic index measures the level of metabolic activityof the thyroid gland in its ability to provide the organism with therequired energetic elements, and this index is defined as follows:Thyroid Metabolic Index=LDH/CPK.

LDH (Lactate dehydrogenase) and CPK (Creatine phosphokinase) are twoenzymes that block insulin access to cells by increasing insulinresistance. Both enzymes reside in muscles and hence reduce their bloodcontent, but they react differently:

a. CPK is typically more impacted than LDH in reaction to an increase ofmetabolic activity because it is immediately mobilized, and hence, itsblood content will be reduced.

b. On the other hand, LDH is typically slower to move and may require anextended adaptation effort to reduce its blood content.

This differentiation in the impact of the thyroid hormones on bothenzymes gives an opportunity to quantify the extent of thyroid metabolicactivity by the ratio LDH//CPK: the higher the thyroid activity, thelower the CPK blood content and the higher the thyroid metabolic index.

**Publication:

Alice Muller et al., Effects of Thyroid Hormone on Growth andDifferentiation of L6 Muscle Cells, Laboratory for physiology, Institutefor cardiovascular research, Free University Amsterdam, The Netherlands.BAM 3 (1): 59-68, 1993.

16. The thyroid yield measures the ratio of the thyroid metabolicactivity versus the pituitary level of solicitation (TSH), and it isdefined as follows: Thyroid Yield=Thyroid Metabolic Index/TSH. Bydefinition, the ratio of the thyroid metabolic index to TSH expressesthe yield of the thyroid in terms of metabolic activity. A low TSH maybe associated with a strong thyroid yield, and conversely, a high TSHmay be associated with a low thyroid yield.

17. The parathormone (PTH) index measures the level of activity of theparathormone, a hormone produced by the parathyroid glands and secretedwhen the blood content of calcium is abnormally low. The parathormoneprimarily serves two tasks:

a. At bone level, it mobilizes the bone calcium by favoring osteolysisof the bone tissue to liberate calcium and phosphatases and increasingosteocalcin blood content.

b. At kidney level, it favors phosphatases elimination by the kidney.The PTH index is defined as: PTH Index=Ca×Osteocalcin/Thyroid YieldIndex.

The PTH index varies like Ca (calcium) and Osteocalcin since their bloodcontent increases with parathormone.

The thyroid has an osteolytic effect similar to the parathormone: if thethyroid yield is high, the parathormone does not need to act andconversely. PTH will vary like the reverse of the Thyroid yield.

18. The osteoclasic index measures the relative part of the osteoclasicactivity of the thyroid, and it is defined as: Osteoclasic Index=LDH/APBone Isoenzymes.

The osteoclasic activity is a catabolic activity (bone destruction).

The index expresses the ratio of LDH, a catabolic action, over thealkaline phosphatases bone isoenzymes, an anabolic indication, of thebone remodeling activity. Thus, the lower the AP bone isoenzymes, thehigher the osteoclasic activity.

The osteoclasic index varies like LDH and like the reverse of the APbone Isoenzymes.

** Publications:

C. Gudmundson et al., Isoenzymes of Lactic Dehydrogenase and Esterasesin Regenerating Bone, Department of Orthopaedic Surgey, Malmö GeneralHospital, University of Lund, Malmö, Sweden, Acta Orthopaedica, 1971,vol. 42, No 4, pp 297-304.

C. Gudmundson et al., Enzyme Studies of Fractures with Normal andDelayed Union, Department of Orthopaedic Surgery, Malmö GeneralHospital, University of Lund, Malmö, Sweden, Acta Orthopaedica, 1971,vol. 42, No. 1, pp 18-27.

Arthur R. Henderson, M. B., Ph.D. et al., Increased Synthesis of LactateDehydrogenase “H” Subunit by a Malignant Tumor, Clin. Chem. 20/11(1974), pp 1466-1469.

19. The osteoblastic index measures the relative part of theosteoblastic activity of the thyroid, and it is defined as: OsteoblasticIndex=CPK/Osteocalcin.

The osteoblastic activity is an anabolic activity (bone remodeling).

This index expresses the ratio of CPK, an anabolic activity (stimulatesthe creation of adenosine triphosphate ATP, a source of immediate energyfor muscles) over osteocalcin blood content, which will reduce when theosteoblastic activity is high, and vice versa.

The osteoblastic index varies like CPK and like the reverse ofOcteocalcin.

** Publications:

B. Fournier et al., Stimulation of Creatine Kinase Specific Activity inHuman Osteoblast and Endometrial Cells by Estrogens and Anti-Estrogensand its Modulation by Calciotropic Hormones, Ciba-Geijy Ltd, Basel,Switzerland, Journal of Endocrinology, 1996, August; 150(2), pp 275-285.

T. Yoshikawa et al., In Vitro Bone Formation Induced byImmunosuppressive Agent Tacrolimus Hydrate (FK506), Department ofOrthopedic Surgery, Nara Medical University, Kashihara, Japan, TissueEng. March/April 2005, 11(3-4), pp 609-617.

20. The turnover index measures the length of the cell renewal cycle interms of the time it takes to get a cell renewal. The higher theturnover index, the slower the renewal, and the lower the turnoverindex, the faster the renewal.

The turnover index is defined as: Turnover Index=TSH×AP Bone Isoenzymes.

TSH indirectly expresses the catabolic activity, necessary for any cellrenewal activity. The lower the TSH, the stronger the thyroid, thefaster the renewal and the lower the turnover index, hence the turnovervaries like TSH.

Relative to the Alkaline phosphatases bone isoenzymes, cell renewal is acatabolic activity and the slower the renewal, the higher the turnover,the higher the anabolism, hence the turnover index varies like thealkaline phosphatases bone isoenzymes, which represents the anabolicactivity, particularly in the osseous area (alkaline phosphatases boneisoenzymes hydrolyse organic phosphatases to produce indissolublemineral phosphatases, hence their notable role in the calcification, atjoints level, and in the mineralization of the skeleton).

In summary the Turnover varies like the product TSH×AP Bone Isoenzymes.

21. The intra-cellular growth index measures the level of intra-cellularactivity of growth factors, and is defined as follows: Intra-cellularGrowth Index=Growth Index/Turnover Index.

The intra-cellular growth index varies like the growth index, adjustedby the speed of cell renewal (turnover index). Thus, when turnover islow (hence fast renewal), the intra-cellular growth activity is high;and conversely, when the turnover is high (hence slow renewal), theintra-cellular growth activity is low.

22. The anti-growth index measures the level of activity of theanti-growth factors, and is defined as: Anti-growthIndex=1/Intra-cellular Growth Index. As reflected in the formula, theanti-growth index varies like the reverse of the intra-cellular growthindex. That is, the higher the intra-cellular growth index, the lowerthe anti-growth activity (and anti-growth index), and vice versa.

23. The somatostatin index measures the level of activity of thesomatostatin and provides a way to assess the overall activity of theexocrine pancreas. The somatostatin index is defined as: SomatostatinIndex=Anti-growth Index/Cortisol Index.

The somatostatin hormone is a strong inhibitor of the growth hormone, asper the research studies referred below. It is one of the mainanti-growth factors and it varies like the anti-growth index.

Cortisol increases growth hormone receptors activity, as per researchstudies referred below, while somatostatin has a reverse effect on thesame receptors, and consequently, the somatostatin index varies like thereverse of the cortisol index.

** Publications:

F. R. Ward et al., The Inhibitory Effect of Somatostatin on GrowthHormone, Insulin, and Glucagon secretion in Diabetes Mellitus, Depts ofReproductive Medicine and Medicine, School of Medicine, University ofCalifornia, San Diego, La Jolla, Calif., USA, Journal of ClinicalEndocrinology & Metabolism (1975), vol. 41, N° 3, pp 527-532.

P. Brazeau et al., Inhibition of GH Secretion in the Rat by SyntheticSomatostatin, The Salk Institute fot Biological Studies, La Jolla,Calif., U.S.A., Journal of Endocrinology (1974), vol. 94, N° 1, pp184-187.

D. Swolin-Eide et al., Cortisol Increases Growth Hormone ReceptorExpression in Human Osteoblast-Like Cells, Research Center forEndocrinology and Metabolism, Dept of Internal Medicine, and Dept ofHand Surgery, Sahlgrenska University Hospital, Goteborg, Sweden, Journalof Endocrinology (1998), vol. 156, Issue 1, pp 99-105.

A. Schonbrunn, Glucocorticoids Down-Regulate Somatostatin receptors onPituitary cells in Culture, Department of Physiology, Harward school ofPublic Health, Boston, Mass., USA, Journal of Endocrinology (1982), vol.110, N° 4, pp 1147-1154.

A. P. Silva et al., Regulation of CRH-Induced Secretion of ACTH andCorticosterone by SOM230 (Somatostatin Analogue) in Rats, NovartisInstitute for BioMedical Research, Basel, Switzerland, European Journalof Endocrinology (2005), vol. 153, Issue 3, pp 7-10.

24. The prolactin index measures the functional activity of theprolactin. This hormone plays a notable role in the reactivation of theadaptation process, influencing catabolism and anabolism, growth andanti-growth factors, at cell and tissular levels.

The prolactin index is defined as: Prolactin Index=SomatostatinIndex×TSH/Growth Index.

The prolactin index varies like the somatostatin index in that prolactinis part of the somatotropic axis and plays a role in balancing growthand anti-growth. It inhibits Growth hormone, hence it varies like thereverse of Growth index.

Prolactin is stimulated by TRH, hence it varies like TSH, alsostimulated by TRH.

25. The insulin index measures the functional activity of insulin and isdefined as: Insulin Index=100×Cata-Ana Index/TSH×Turnover Index.

The insulin, in its role of bringing immediate energy through theinitial adaptation syndrom, varies like the Cata-Ana index, whichrepresents the mobilization of factors participating in the set up ofthe immediate defense system.

Insulin acts also along the thyroid in its role of mobilizing energeticreserves, and hence, it varies like the reverse of TSH (a strong TSH,hence a weak thyroid, inhibits insulin; and conversely, a weak TSH,hence a strong thyroid, increases insulin).

A third role of insulin is to increase cell nutrition to support cellrenewal and growth, and hence, it varies like the reverse of theturnover index: a low turnover is a sign of fast cell renewal hence anincrease of cell nutrition and an increase of insulin, conversely, anincrease of turnover decreases insulin activity.

The factor 100 has been added to maintain the index in a bandwithsimilar to other related indexes.

Consequently, the insulin index varies like the Cata-Ana index and likethe reverse of TSH and Turnover, with an adjustment factor of 100.

** Publications:

V. Lafargia et al., The Effects of Insulin on TSH Secretion and theMorphology and Physiology of the Thyroid in the Lizard Podarcis Sicula,Department of Comparative Biology, Universita degli Studi di Napoli,Naples, Italy, Amphibia-Reptillia (1996), vol. 17, no. 1, pp. 39-45.

R. P. Lamberton et al., Insulin Hypoglycemia Suppresses TSH Secretion inMan, Tufts New England Medical Center Hospital, Boston, Mass., USA,Hormone and Metabolic Research, vol. 18, no. 1, pp. 76-77 (1986).

26. The insulin resistance index measures the inhibition level of theinsulin activity at the membrane level, independent of its temporaryactivity linked with the general adaptation syndrome. It is defined as:Insulin Resistance Index=Somatostatin Index/Insulin Index.

As insulin resistance is a growth hormone inhibitor at the cell level,the insulin resistance index varies like somatostatin.

Conversely, the Insulin resistance index varies like the reverse ofinsulin, outside of adaptation (the insulin resistance index decreaseswhen insulin is high in order to facilitate the glucose access to cells,and it increases when insulin is low).

In instances of stress, Insulin resistance may selectively preventglucose access to cells in non-priority organs in order to secure theenergy distribution to priority organs (heart, brain, muscles).

27. The demyelination index measures the adaptative activity of insulinin its timing relationship to the adaptative activity of the growthhormone, and it is defined as:

Demyelination Index=Insulin Index/(Growth Index×Intra-cell GrowthIndex).

The demyelination index expresses the chronology insulin-growth factors,i.e., the demyelination increases when insulin anticipates on growthfactors, under the influence of glucagon.

Also present in the demyelination index, the growth index and theintra-cell growth index: both express the same thing in terms of growthhormone activity or in terms of cell growth. They amplify thedemyelination risk (the lower the growth hormone or the intra-cellgrowth, relative to insulin, the higher the demyelination risk).

28. The next number of example indexes describes the cell activitybetween the nucleus and the membrane, as well as the various types ofcellular death. These indexes include a nuclear/membrane index, membraneexpansion rate, structural expansion rate, membrane fracture rate,apoptosis rate, necrosis rate and fibrosis rate.

28-1. The nuclear/membrane index measures the level of metabolicactivity of the nucleus relative to the membrane activity, and isdefined as: Nuclear/Membrane Index=Metabolic Estrogens Index/GrowthIndex.

The focus target of estrogens metabolic activity is the nucleus, whilethe focus target of the growth hormone metabolic activity is themembrane.

By definition the nuclear/membrane index is the ratio of the estrogensmetabolic activity index over the growth hormone activity index, whichhas a respective impact on cell Nucleus and membrane.

28-2. The membrane expansion rate measures the metabolic activity of themembrane, and is defined as: Membrane Expansion Rate=CatabolismRate×Intra-cell Growth Index.

In this index, the catabolism rate is the starting point of any cellmembrane expansion, and the intra-cell growth index represents theintra-cell activity of growth factors.

Both indexes have an amplification impact on the Membrane expansion.

A strong membrane expansion rate represents a strong dominance of growthfactors over structural factors: the higher it is and the higher is therisk of membrane fracture leading to necrosis (see below).

Notably, the catabolism rate is yet another index, which is defined asthe ratio of the thyroid metabolic index to the adrenal gland index(Catabolism Rate=Thyroid Metabolic Index/Adrenal Gland index).

In this regard, catabolism depends almost in large part upon the thyroidmetabolic activity, and logically it varies like the thyroid metabolicindex.

Also, adrenal hormones favor both anabolism through adaptation andcatabolism through permissivity over the thyroid. The adrenal glandindex functions as a moderating factor in the catabolism rate indexsince a strong glucocorticoid response usually generates anhypo-catabolism, hence the catabolism rate varies like the reverse ofadrenal gland activity.

28-3. The structural expansion rate measures the metabolic activity ofthe nucleus. The structural expansion rate index is defined as follows:Structural Expansion Rate=Anabolism Rate Index×Nuclear/Membrane Index.

For this index, the anabolism rate, which represents the anabolismmetabolic activity driven by estrogens over the nucleus, is defined byCatabolism rate/Cata-Ana Index. The nuclear/membrane index representsthe level of metabolic activity of the nucleus relative to the membraneactivity. And similar to the membrane expansion rate, both above indexeshave an amplification impact on the structural expansion rate.

28-4. The membrane fracture rate measures the degree of fragility of themembranes and hence their risk of fracture. It is defined as: MembraneFracture Rate=Metabolic Yield Index/(TSH×Turnover Index).

Overall metabolic activity is required to support a membrane expansion,and as such, the membrane fracture rate varies like the overallmetabolic yield which is the sum of both catabolic and anabolicactivities.

Membrane fracture also requires strong thyroid activity, the higher thethyroid throughput, the lower the TSH—and hence, the membrane fracturerate varies like the reverse of the TSH.

Finally, membrane fracture is the consequence of a fast cell renewal(the faster the cell renewal, the lower the turnover). And consequentlythe membrane fracture rate varies like the reverse of the Turnoverindex.

28-5. The apoptosis rate measures the level of apoptosic activity forthe whole organism. It is an indication of nucleus overactivity andacceleration of cell growth process. The apoptosis rate increases whenthe cell growth is normal, and decreases when the cell growth isabnormal or when the organism is in a deceleration of growth. Theapoptosis rate is defined as: Apoptosis Rate=Structural ExpansionRate/Membrane Expansion Rate.

The structural expansion rate represents the metabolic activity of thenucleus (the higher the structural expansion rate, the higher thelikelihood the cell is in a programmed death, for a limited number ofdivisions. Apoptosis, which measures the cell programmed death activity,varies like the structural expansion rate.

Apoptosis varies like the reverse of the membrane expansion rate. Thehigher the membrane expansion rate, the lower the apoptosis and thehigher the risk of membrane fracture (with cell implosion leading tonecrosis instead of apoptosis), and vice versa.

28-6. The necrosis rate measures the level of cellular implosion bynecrosis relative to apoptosis. It is the other type of cellular death,with waste, generally associated with local inflammation. The necrosisrate is defined as: Necrosis Rate=Membrane Fracture Rate/Apoptosis Rate.As necrosis is a consequence of membrane fracture, the necrosis ratevaries like the membrane fracture rate. And as the definition of thenecrosis rate is relative to apoptosis, the necrosis rate varies likethe reverse of the apoptosis rate.

28-7. The fibrosis rate measures the fibrosis activity of the organism,from a simple isolation of a tissue to a degenerative sclerosis of a setof tissues or an organ. Fibrosis is part of the growth process: itparticipates in organ growth in order to prevent excessive growth. Thefibrosis rate is defined as: Fibrosis RateIndex=(TSH)²×(Osteocalcin)³/100. In this formula, the power used forboth TSH and osteocalcin differentiates the relative weight of bothcomponents in the measurement of the fibrosis activity. The 100denominator keeps the index in a normal bandwidth relative to otherindexes.

The fibrosis rate varies like the TSH. In this regard, as fibrosis is ananti-growth factor, it is typically favored by a weak thyroid, andhence, a strong TSH.

Similarly, fibrosis rate varies like the reverse of bone osteocalcin. Astrong fibrosis is linked with an imbalance of the calcium metabolismassociated with a decrease of the osteocalcin in the fibrosed area,hence an increase of the osteocalcin blood content. Fibrosis will varylike the osteocalcin blood content.

Having introduced a number of example indexes of the BiologicalSimulation Model, the following discussion presents a number of examplecases in which one or more indexes have been tested in relation to oneor more pathologies, some of which also illustrate the effects ofclassical treatments on the indexes.

4-2. Testing the Biological Simulation Model on Pathologies

As described herein, testing the Biological Simulation Model onpathologies may be sub-divided as follows:

4-2-1. Testing One Index and One Pathology:

Example Case 1: Histamine index and Eczema,

Example Case 2: Histamine index and Rhinitis,

Example Case 3: Demyelination index and Multiple Sclerosis,

Example Case 4: Insulin index and Mucoviscidosis,

Example Case 5: Insulin resistance index and Down syndrome,

Example Case 6: Bone remodeling index and Bone metastases, and

Example Case 7: Bone remodeling index and Osteoporosis.

4-2-2. Evaluation of Classical Treatments:

Example Case 8: LH RH analogues over FSH/LH and androgens,

Example Case 9: Chemotherapy over Histamine, and

Example Case 10: Cortisone on Chronic allergy (asthma).

4-2-3. Multiple Patients with One Pathology:

Example Case 11: Fibromyalgia (20 sick versus 20 healthy).

4-2-4. Major Relevant Indexes for a Given Pathology:

Example Case 12: Metastasized Colon cancer, and

Example Case 13: Metastasized Prostate cancer.

4-2-1: Testing One Index and One Pathology

In the following seven example cases, one index has been tested inrelation to one pathology.

Example Case 1 Histamine Index and Eczema

In this first example, consider the case of a six-year-old femalesuffering from generalized eczema at the time of her first consultationon Apr. 30, 2003. The patient's father is cutaneous allergic, and thepatient has been previously diagnosed with asthma (treated by Becotideand Ventoline) and chronic rhinopharyngitis. The patient was firstdiagnosed with generalized eczema at age eighteen months, and hadpreviously been treated (without success) with local corticoids.

Following her first consultation, the patient was given a terraintreatment and experienced a complete healing in two months. Her healingwas confirmed by blood analysis at a second consultation on Sep. 27,2003, at which time her histamine index levels also dropped to withindesignated normal levels for a female, as reflected in the below table.

Female Norms Date 2003 Apr. 30 2003 Sep. 27 Mini W Maxi W HistamineIndex 387 55 20 60

** Publication:

J. Ring, Plasma Histamine Concentrations in Atopic Eczema, DermatologyDepartment, Ludwig Maximilians University Munich, West Germany, ClinAllergy, 1983 November, 13(6): pp 545-52.

Example Case 2 Histamine Index and Allergic Rhinitis

In a second example, consider the case of a forty-two-year-old female atthe time of her first consultation in January 2003. Since puberty, thepatient has suffered from a chronic rhinitis with seasonal allergicsymptoms. The patient has received various treatments (corticoids,antiallergic drugs, beta-stimulants) with limited success. Butchronicity has increased through time, with symptoms becoming permanent,such as full nasal obstruction, postnasal drips and very frequentsneezing.

Analysis of the patient's blood work shows a very high histamine indexat 1085 versus designated norm levels for a female from 20 to 60. Anappropriate treatment reduced the index by eighty-five percent over ayear period: the signs of rhinopharyngitis have fully disappeared andthe patient feels a complete healing. No relapse during a six-yearperiod following the patient's first consultation. The data belowillustrate the patient's histamine index at her first consultation, andat second and third subsequent consultations—the second and thirdconsultations occurring approximately four months and one year,respectively, after the first consultation.

Female Norms Date 2003 Jan. 13 2003 May 12 2004 Jan. 5 Mini W Maxi WHistamine 1085 889 157 20 60 Index

** Publication:

A. Weyer et al., Seasonal Increase of Spontaneous Histamine Release inWashed Leucocytes from Rhinitis Patients Sensitive to Grass Pollen,Unité d'Immuno-Allergie, Institut Pasteur, Paris, France, Clin ExpImmunol, 1990 March, 79(3): 385-391.

Example Case 3 Demyelination Index and Multiple Sclerosis

In a third example, consider the case of a twenty-eight-year-old malewho since 1993 has suffered from chronic sensitivity disorders at thelevel of limbs and thorax, a type of multiple sclerosis (MS). Thepatient has experienced chronic relapses of symptoms requiring corticoidtreatment over short period of time. In July 1995, the patient sufferedretrobulbar optic nevritis on his left eye, which was treated byhigh-dose corticosteroid embolization. And beginning in 1998, thepatient has been treated with Interferon Beta since 1998, one injectionper week.

As can be seen in the graph of FIG. 1, the demyelination index for thispatient is strictly correlated with the time of activation of thepathology, i.e., August 1999, August 2001, November 2003, October 2005,January 2007 and June 2008.

** Publication:

Cortical Demyelination and Diffuse White Matter Injury In MultipleSclerosis,

Kutzelnigg A, Lucchinetti C F, Stadelmann C, Brück W, Rauschka H,Bergmann M, Schmidbauer M, Parisi J E, Lassmann H.,

-   -   Center for Brain Research, Medical University of Vienna, Vienna,        Austria, Brain, 2005 November; 128(Pt 11): 2705-12. Epub 2005        Oct. 17.

Example Case 4 Insulin Index and Mucoviscidosis (Cystic Fibrosis)

In a fourth example, consider the cases of two patients previouslydiagnosed with cystic fibrosis, and a third patient experiencing similarinsulin index levels.

The first case is of a five-year-old male diagnosed with cystic fibrosisat the age of two. As shown in the table below, the trend of the insulinindex over a five and one-half year period shows a stable picture at avery low level. More particularly, the trend shows that the insulinindex averages 10% of the designated normal levels (1.5 to 5.0), withnearly identical levels at beginning of the period (0.15 in November2003) and end of the period (0.12 in May 2009).

Mini/Maxi Norms: 1.5 to 5.0

November November October May Case 1 2003 2004 2005 2006 May 2007 May2009 Insulin 0.15 0.08 0.25 0.32 0.12 0.12 index

The second case is of a four-and-one-half-year-old female diagnosed withcystic fibrosis at the age of one. As shown in the table below, theinsulin index is below the designated normal levels (1.5 to 6.0) at thetime of her first consultation and tends to decrease gradually throughtime over a four-year period.

Mini/Maxi Norms: 1.5 to 5.0

July July June Case 2 2005 2006 2007 May 2008 June 2009 November 2009Insulin 1.05 0.34 0.28 0.20 0.45 0.30 index

And the third case is of a seventeen-year-old female not previouslydiagnosed with cystic fibrosis. As shown in the table below, the insulinindex for this patient is also significantly below the designated normallevels (1.5 to 6.0), confirming the two previous cases of cysticfibrosis with low insulinic activity, and being confirmed by Researchstudies, as stated below

Male/Female Norms Date January 1999 Mini Maxi Insulin index 0.45 1.5 5

** Publication:

E. M. Laursen et al., Diminished Concentrations of Insulin-Like GrowthFactor I in Cystic Fibrosis, Dept of Growth and Reproduction GR, StateUniversity Hospital, Copenhagen, Denmark, Arch Dis Child 1995;72:494-497 doi:10.1136/adc.72.6.494.

Example Case 5 Insulinic Resistance and Down Syndrome

In a fifth example, consider the case of a male with Down syndrome. Asshown in the table below, the patient has an insulin resistance indexthat consistently trends at very high levels relative to the designatednormal levels, at least in the in the early phase of childhood,confirmed by Research studies as stated below.

Date January 2007 May 2008 January 2009 September 2009 Male Norms Age(years) 2 3 5/12 4¼ 4⅚ Min Max Insulin Resistance 13212 307 1163 10500.75 1.25

** Publications:

E. J., Hoorn et al., Insulin Resistance in an 18-Year-Old Patient withDown Syndrome Presenting with Hyperglycaemic Coma, Hypernatraemia andRhabdomyolysis (Case Report), Erasmus Medical Center, Rotterdam, TheNetherlands, Journal of internal medicine, 2005, vol. 258, n° 3, pp.285-288 [4 page(s) (article)] (19 ref.).

C. T. Fonseca et al., Insulin Resistance in Adolescents with DownSyndrome: A Cross Sectional Study, Medicina School, HUCFF, FederalUniversity of Rio de Janeiro, Brazil, Genetics dept, IPPMG, Ilha deFundao, Rio de Janeiro, Brazil, Pediatrics Dept, HUCGG, Ilha de Fundao,Rio de Janeiro, Brazil, Endocrinology Dept, HUCFF, Ilha de Fundao, Tiode Janeiro, Brazil, BMC Endocrine Disorders 2005, vol. 5 PubMeddoi:10.1186/1472-6823-5-6.

Example Case 6 Bone Remodeling and Osseous Metastases

In a sixth example, consider the cases of two patients. The firstpatient was, at the time of his first consultation in July 2000, afifty-nine-year-old male diagnosed seven years prior with prostatecancer undergoing hormonotherapy treatment. In July 2000, the patientwas suffering from paraplegia of the lower extremities, with destructionof D9 vertebra and compressive external pachymeningitis. Generalizedosseous metastases is discovered and treated with radiotherapy. Thepatient died in November 2000, approximately four months following hisfirst consultation.

As shown in the table below, the patient's bone remodeling index surgedfrom the patient's first consultation through two subsequentconsultations, thereby giving an indication of the speed of the cancerosseous expansion.

Male Norms Date July 2000 August 2000 October 2000 Mini Maxi BoneRemodel Index 43 33 115 2.5 8.5

At the time of his first consultation in January 2007, the secondpatient was a sixty-four-year-old male. Eight years earlier, in October1998, a PSA control yielded a level of 85 ng/ml (norm<5.0), indicating apoorly-differentiated prostate adenocarcinoma, with extension to theright seminal vesicle. The patient was treated with radiotherapy offorty-five grays over the prostate and twenty-five grays over the pelvisarea. In December 1998, a lymphadecnotomy revealed a contaminatedilio-obturator lymph node, for which the patient was treated with asingle injection of LH RH analogue for three months, and then Casodex(three capsules per day) for several years. Then, in July 2006, thepatient's PSA level showed a gradual increase, leading to additionalradiotherapy on the pelvic area (eight sessions).

At the time of the second patient's first consultation in January 2007,the patent was suffering from multiple metastases concerning ureterswith bilateral pulmonary metastases. Approximately eleven monthsthereafter, in December 2007, the patient died following a renalblocking secondary to the bilateral ureteral metastatic obstruction. Thetable below shows the bone remodeling index for the second patient for aportion of the final year of the patient's life. As shown, the boneremodeling index trend shows some temporary improvement during 2007,until the organism started escaping from the treatment in October 2007.

Male Norms: 2.5 to 8.5

Date January March May August September December 2007 2007 2007 20072007 2007 Bone 62 36 25 16 17 80 Remodel Index

Example Case 7 Bone Remodeling and Osteoporosis

In a seventh example, consider the case of a fifty-five-year-old femaleat the time of her first consultation in May 2009. For approximatelyfour years prior, beginning in 2005, the patient had undergone hormonereplacement therapy for menopause, and undergone Utrogestan, Estrogel,vitamin D and calcium treatment for spinal osteoporosis, although herinitial bone remodeling was normal. In August 2009, the patient suffereda crush fracture of her T6 vertebra with low bone mineral densitydiffused through the entire vertebral body.

As shown in the graph of FIG. 2, for a period of approximately fourmonths before the patient suffered the crush fracture, the patient'sbone remodeling index decreased from an already low level of 0.72 inJanuary 2009 to 0.29 in May 2009 (from norm levels between 2.5 and8.5)—explaining the crush fracture that the patient would sufferapproximately three months later.

The table below illustrates the results of an osteodensitometryprocedure performed on the patient approximately four months after shesuffered the crush fracture. The procedure confirmed the magnitude ofbone loss. The patient's Bone Mineral Density (BMD) tested at 0.651g/cm2, which is 25% lower than the average woman of the patient's sameage (−2.0 Standard Deviations SD).

Osteodensitometry cv BMD T Score Z Score Percentile (Dec. 4, 2009) (%)(g/cm2) (SD) (SD) (%) Thigh Bone total zone 0.8 0.874 −1.3 −0.5 31cervical zone 1.7 0.66 −1.9 −0.6 27 ward zone 2.6 0.515 −2.3 −0.5 31Forearm ultra distal zone 1 0.36 −0.5 0 50 proximal zone 1.5 0.658 0.20.9 82 Front rachis exam 0.9 0.651 −3.4 −2 2 BMD observed 0.651

** Publications:

Bone Remodeling in Osteoporosis,

M. C. de Vernejoul,

-   -   INSERM U18, Hôpital Lariboisière, 6 rue Guy Patin, 75010 Paris,        France, Clinical Rheumatology, vol. 8, Supplement 2/June 1989.

Bone Marrow, Cytokines, and Bone Remodeling—Emerging Insights into ThePathophysiology Of Osteoporosis,

S C Manolagas, M.D., Ph.D., and R L Jilka, Ph.D., Dept of InternalMedicine, University of Arkansa for Ledical Sciences, Little Rock, USA,The new England Journal of Medicine, vol. 332:305-311, N° 5, Feb. 2,1995.

4-2-2: Evaluation of Classical Treatments

The following next three example cases illustrate the effects ofclassical treatments on the indexes.

Example Case 8 Effects of LH RH Analogs(Decapeptyl/Triptorelin/Leuprolide) Treatment over FSH, LH and Androgens

In this eighth example, consider the case of a sixty-two-year-old maleat the time of his first consultation in December 2008. In April 2004,the patient underwent a radical prostatectomy with lymph nodesdissection. The patient had also twice undergone chemotherapy treatment,first using Taxotere® for a three-month period from August to November2006, and then using Zometa® for a three month period from May to August2007. In December 2007, approximately a year before his firstconsultation, the patient was also diagnosed with multiple osseousmetastases, which had been treated with Sutent® (37.5 mg/day).

The graphs of FIGS. 3, 4 and 5 show the blocking effects of an injectionof Decapeptyl (Triptorelin) given Jun. 1, 2009 (about six months afterthe patient's first consultation), over FSH, LH, tissular androgenic andDHEA activities.

FIG. 3 illustrates FSH and LH indexes (norms 0.3 to 8.0). Both curvesshow the effect of the Triptoreline injection on June 1st reducing by afactor E7 between March and August, with a rebound in November, when theinjection is 6 months old.

FIG. 4 illustrates tissular androgen activity (norms 0.09 to 0.13), andshows a similar kind of drop from 1.08 to 0.01 between March and August,with a rebound in November when the injection is 6 months old.

FIG. 5 illustrates the DHEA activity index (norms 2 to 6), and shows asimilar kind of drop from 2.0 to 6.5 E-7 between March and August, witha rebound in November, when the injection is 6 months old.

** Publications:

Comparative Efficacy of Triptorelin Pamoate and Leuprolide Acetate inMen with Advanced Prostate Cancer,

-   -   South African Triptorelin Study Group: C F Heyns, M L Samonin, P        Grosgurin, R Schall. C H Porchet,

Dept of Urology University of Stellenbosch, Tygerberg Hospital, WesternCape, South Africa,

Debiopharm S A, Lausanne, Switzerland,

Quintiles ClinData, Bloemfontein, South Africa,

BJU international, 2003, vol. 92, n° 3, pp. 226-231.

Leuprolide Acetate: A Drug of Diverse Clinical Applications,

A C Wilson, S Vadakkadath Meethal, R Bowen, C S Atwood,

Dept of Medicine and Geriatric Research, University of Wisconsin,Madison Wis., USA,

Dept of Pathology and Laboratory Medicine, Madison Wis., USA,

ORB Research, Charleston S.C., USA,

Case Western University, Cleveland Ohio, USA,

Expert Opinion on Investigational Drugs, vol. 16, no. 11, November 2007,pp. 1851-1863(13).

Comparative Efficacy of Triptorelin Pamoate and Leuprolide Acetate inMen with Advanced Prostate Cancer,

South African Triptorelin Study Group: C F Heyns, M L Samonin, PGrosgurin, R Schall. C H Porchet,

Dept of Urology University of Stellenbosch, Tygerberg Hospital, WesternCape, South Africa,

Debiopharm S A, Lausanne, Switzerland,

Quintiles ClinData, Bloemfontein, South Africa,

BJU international, 2003, vol. 92, n° 3, pp. 226-231.

Leuprolide Acetate: A Drug of Diverse Clinical Applications,

A C Wilson, S Vadakkadath Meethal, R Bowen, C S Atwood,

Dept of Medicine and Geriatric Research, University of Wisconsin,Madison Wis., USA,

Dept of Pathology and Laboratory Medicine, Madison Wis., USA,

ORB Research, Charleston S.C., USA,

Case Western University, Cleveland Ohio, USA,

Expert Opinion on Investigational Drugs, vol. 16, no. 11, November 2007,pp. 1851-1863(13).

Example Case 9 Chemotherapy and Histamine Induction in a Cancer Patient

In a ninth example, consider the case of a female who in June 2002, atthe age of forty seven, underwent a full right breast mastectomy, withauxilary curage of four metastatic lymph nodes with capsule tear, amongsix identified lymph nodes (4N+/4R+/6). As to the patient's histology:she had an infiltrating ductal carcinoma SBR (Scarff-Bloom-Richardson)grade I, 4 cm long, concerning the area behind the nipple and externalquadrants, and infiltrating the nipple, with colonization of theepidermis on surface. The patient also had a noticeable a smallinfiltrating carcinoma 8 mm long at a distance of the external quadrantsjunction. The limits of ablation were healthy tissue.

An immunohistochemical analysis showed that the infiltrating carcinomawas Estrogen Receptor negative and slightly Progesterone Receptorpositive.

In addition, between August and November 2002, the patient underwentadjuvant chemotherapy treatment made of six cycles, based on Adriamycin(86.5 mg), Ifosfamide (1165 mg) and Taxotere® (130 mg) within a BCIRG005protocol. The patient did not take any other medication or undergo anyother treatment, including cortisone, antiemetic or stimulating of bonemarrow.

FIG. 6 illustrates the patient's histamine index over a period of time,with the arrows indicating the dates of the patient's chemo sessions. Asshown, the dates of the chemo sessions are indicated by arrows on thegraph (August 8, August 29, September 19, October 10, October 31,November 21, all 2002).

The illustrated histamine index trend shows a peak after perfusion and asubsequent return to the basal state, which is getting more and moredifficult through time, until the chemotherapy ends. This may open newopportunities for tracking patients under chemotherapy treatment. Inthis regard, the time to get to the peak of the histamine reaction andits intensity may permit one to identify a patient's risks to stronghistaminic reactions with their associated effects (e.g., nauseas,vomiting, cephalgias, various allergies, etc.) and, if desired, apply acorrective complementary therapy.

Publication:

Effect of Paclitaxel (Taxol) and Its Solvent Cremophor EL on Mast CellHistamine Secretion and Their Interaction with Adriamycin,

G Decorti, B F Klugman, L Candussio, L Baldini,

Department of Biomedical Sciences, Faculty of Medicine, Trieste, Italy,

Anticancer Res 1996 January-February, vol. 16, N° 1, pp 317-320.

Example Case 10 Effect of Cortisone on Chronic Allergy (Asthma)

In a tenth example, consider the case of a sixty-two-year-old femalewith osteoporosis and multiple food intolerances, and who has sufferedfrom asthma since childhood. The patient is given cortisone (60 mg/day)for two months prior to a consultation on Apr. 19, 2010. The patient'srelated index evolution between Jan. 26, 2010 and Apr. 19, 2010, and theconsultation looks as follows:

Female Norms Index 2010 Jan. 26 2010 Apr. 19 Mini Maxi Cortisol 0.4 14.53 7 ACTH 676004 0.25 0.7 3 DHEA 251080 4 5 9 Adaptation Ratio 3.30 0.160.25 0.5 (Eosinophils) 22.1 1.3 1 5 Histamine 11969 15 20 60 BoneRemodeling 8 27 2.5 8.5 Parathormone 16.9 3.1 2 42

As shown in the above table, as a consequence of the cortisonetreatment, the cortisol jumps by a very large factor (over 30). Exampleembodiments of the present invention can detect a high level of cortisolwithout measuring it in the blood. Relative to the ACTH index,physiological studies (as referred below) have demonstrated that anupsurge in cortisol blocks the ACTH, which maybe identified by exampleembodiments without measuring it in blood. As also shown, DHEA beingunder control of ACTH, the DHEA index sharply declines, together withACTH, as indicated by its measurement. Further, the increase in cortisolresults in a significant reduction in the eosinophils, and consequentlya decrease in the histamine index. And a large increase in cortisol,through its catabolic effect on bone, may increase the bone remodelingindex, coupled with a significant decrease of parathormone, in reactionto the liberation of calcium by the bone catabolism. The related indexesshow a large consistency with the physiological moves identified inResearch papers listed below.

** Publications:

Alterations in Cortisol Negative Feedback Inhibition as Examined Usingthe ACTH Response to Cortisol Administration in PTSD,

R Yehuda, R K Yang, M S Buchsbaum, J A Goller,

The Traumatic Stress Studies Program, Psychiatry Department, Mount SinaiSchool of Medicine, and the Bronx Veterans Affairs Medical Center, 130West Kingsbridge Road, Bronx, N.Y. 10468, USA,

Psychoneuroendocrinology (2006) May; 31(4): pp 447-451.

Effect of ACTH and Prolactin on Dehydroepiandrosterone (DHEA), ItsSulfate Ester and Cortisol Production by Normal and Tumorous HumanAdrenocortical Cells,

T Feher, K S Szalay, and G Szilagyi,

Hungarian Academy of Sciences, Postgraduate Medical School andSemmelweis University Medical School, Budapest, Hungary,

Journal Steroid Biochemistry (1985) August; 23(2): pp 153-157.

Eosinophils Activate Mast Cells to release Histamine,

A M Piliponsky, D Pickholtz, G J Gleich, F Levi-Schaeffer,

Dept of Pharmacology, School of Pharmacy, The Hebrew University-HassadMedical School, Jerusalem, Israel,

-   -   Dept of Immunology, Mayo Clinic and Foundation, Tochester,        Minn., USA, Int. Arch Allergy Immunology (1999) 118, N) 2-4, pp        202-203.

Profiles of Endogenous Circulating Cortisol and Bone Mineral in HealthyElderly Men,

E. Dennison, P. Hindmarsh, C. Fall, S Kellingway, D Barker, D Philipsand C Cooper,

Medical Research Council Environmental Epidemiology Unit, University ofSouthampton, Southampton General Hospital, Southampton, UK,

Cobbold Laboratories, Middlesex Hospital, London, UK,

The Journal of Clinical Endocrinology & Metabolism (1999),

Journal of Endocrinology (2009) 201, pp 241-252Vol 84, N° 9, pp.3058-3063.

Cortisol Mobilizes Mineral Stores from Vertebral Skeleton In TheEuropean Eel: an Ancestral Origin for Glucocorticoid-InducedOsteoporosis,

M Sbaihi, K Rousseau, S Baloche, F Meunier, M Fouchereau-Peron, and SDufour,

Museum Natioal d'Histoire Naturelle, Paris, France,

Marine Station of Concarneau, Concarneau, France.

4-2-3: Multiple Patients with One Pathology Example Case 11 Study ofFibromyalgia Cases versus Healthy Cases (2×20)

In the following eleventh example case, multiple patients with onepathology are evaluated. In this example, consider a sampling of twentyfemales aged between 30 and sixty (with one-third from 40 to 50) whosuffer from fibromyalgia, and a similar sampling of twenty healthyfemales. In the patients with fibromyalgia, the most commonly-observedsymptoms include: muscular pains and inflammatory lesions, abdominalpains, insomnia, headaches, anxiety and depression, gastro-oesophagealreflux disease (GERD) and chronic fatigue.

The Biological Simulation Model of example embodiments of the presentinvention identified in the patients with fibromyalgia a number of areasof endocrine imbalance, as illustrated in the below table. For example,these patients had an excess of aldosterone that may create swellingsand peripheral edemas, and an excess of peripheric serotonin (shortageof central serotonin) that may create depression, migraines, headachesheadaches and gastro-intestinal troubles (GERD). These patients alsoexhibited the following: a shortage of somatostatin (hypo function ofexocrine pancreas), an excess of insulin, relative to insulinicresistance, an excess of intra-cell insulinic activity: high cellpermeability and osmolarity, and an excess of oxidoreduction and freeradicals.

Median Values Female Norms Index Healthy Fibromyalgia Mini MaxiAldosterone 756 10818 77 2688 Peripheral Serotonin 5.1 26.2 1.5 7.5Somatostatin 1.9 0.5 1.5 5.0 Insulin versus Insulin resistance 2.9 43.82 4 Intra-cell insulinic activity 4.6 47.9 8 12 (cell osmolarity)Oxidoreduction 0.4 2934 0.7 2.0 Free Radicals excess 10 4848 2 6

This eleventh example illustrates the multiplicity of the dysfunctionsunderlying the broad scope of the fibromyalgia syndrome observed in agroup of patients. For a given patient, the distribution of the relevantindexes, coupled with the clinical examination, may permit one todevelop the appropriate therapeutic. For example, a patient may betreated to reduce aldosterone if the patient is suffering from swellingsand peripheral edemas, and/or treated with supporting central serotoninif the patient is suffering from neurologic troubles (depression,headaches, etc.). The majority of patients suffer from metabolictroubles associated with a cell overnutrition affecting the muscles,associated with a hypofunctioning of the exocrine pancreas (lowsomatostatin), and coupled with an excess of oxidation and freeradicals. For fibromyalgia, as for kinds of syndromes, exampleembodiments of the present invention permit an extended study of thepathology, which affects a large part of the population, by working onmuch larger samples in order to break the broadly called “fibromyalgiasyndrome” in homogeneous pathology subsets, with repeatable symptoms anddysfunctions, which permits to associate adequate therapeutics.

4-2-4: Major Relevant Indexes for a Given Pathology

The following example cases evaluate the major relevant indexes for agiven pathology.

Example Case 12 Evolution of a Metastasized Colon Cancer

In a twelfth example, consider the case of a forty-six-year-old femalewith the following antecedents: cousin diagnosed with rectum cancer atage 50, paternal grandmother diagnosed with colon cancer at age 50, andmaternal aunt diagnosed with breast cancer and colon cancer at age 60.On Jul. 9, 2008 a right colon tumor (tubulovillous adenocarcinoma stageT1-M2, with lymph nodes metastases (5)) was identified through acoloscopy. Then, on Jul. 29, 2008, the patient underwent a rightileocolectomy, which was followed by chemotherapy (six cycles of Folfox)ending in February 2009. On Jun. 2, 2009, the patient underwent athoraco-abdomino-pelvian scan, from which three hepatic lesions wereidentified in the right side of liver (confirmed three days later by aPET scan). The patient was then again given chemotherapy treatment(three cycles of Folfori-Avestin), ending in July 2009. On Aug. 27,2009, the patient underwent a right hepatectomy to clear metastases fromthe colon cancer, and from Sep. 15, 2009 to Feb. 3, 2010, the patientwas yet again given chemotherapy (eleven cycles of Folfori-Avestin).

On Nov. 24, 2009, a CT scan (chest/abdomen/pelvis) of the patient cameback normal, as did a similar scan on Feb. 9, 2010. On Mar. 11, 2010,however, a PET (positron emission tomography) scan showed multipledisseminated hypermetabolic lesions (retro-peritoneal, Virchow's nodes,a right hilar-pulmonary and a new hepatic lesion). And on Apr. 12, 2010,a rachis MRI and a CT scan (abdomen/pelvis) showed spin bone lesions atthe lombar level, multiple disseminated hepatic and nodular lesions,compression of the intra-hepatic bile ducts and an intra-hepaticdilatation.

The classical biological data and related index evolution across threemilestones: July 2009, March 2010 and April 2010 for this patient areshown in the below table.

2009 Jul. 16 2010 Mar. 8 2010 Apr. 15 Mini Maxi Lab Data LDH 347 438 787266 500 Osteocalcin 17 7 3 11 43 Alkaline 37 243 860 35 104 PhosphatasesCEA 2.6 3.5 13.3 10 CA 125 18.8 178.5 35 SGOT 36 84 164 5 45 SGPT 60 135335 5 35 GGT 38 486 1273 35 Index Cata-Ana 0.4 4.2 9.8 1.8 3 Growth 2 32229 2 6 Somatostatin 16.9 0.4 0.3 1.5 5 Turnover 11 105 484 40 60 Bone 368 727 2.5 8.5 Remodeling Metabolic 0.3 1.4 4.8 0.2 0.4 EstrogenbMSH/aMSH 6.2 4.8 21.3 6 8 Thyroid 4.6 3.8 15.7 3.5 5.5 Metabolic PTH6.4 4 0.6 2.5 42.4 Apoptosis 2.46 0.03 0.004 0.3 0.7

After eleven cycles of chemotherapy from September 2009 to Feb. 3, 2010,the patient seemed to be cancer free as evidenced by a normal CT scan(chest/abdomen/pelvis) on Feb. 9, 2010. On that basis, chemotherapy wasterminated. One month later, based on March 8 data, the BiologicalSimulation Model of example embodiments of the present invention showeda sharp degradation of the state of the patient, a few days before theMarch 11 PET scan showed a spreading of the pathology.

In July 2009, there were only three small hepatic lesions on the rightside of the liver, which were extracted the following month (righthepatectomy in August 2009), without other signs of extension. Classicallab data shows no out of line situation, except a slight increase ofSGPT transaminases and gamma GT, consistent with the state of the liver.The Biological Simulation Model of example embodiments of the presentinvention, on the other hand, shows that the potential of anti-growthfactors are still strong (high somatostatin at 16.9), a balanced cellrenewal favoring normal cell development (low turnover and highapoptosis), and normal cellular activity (balanced beta/alphasympathetic), without metabolic outburst (normal estrogenic andthyroidian activity). These elements of the Biological Simulation Modelsuggest good control of the organism over the pathology.

On Mar. 8, 2010, only one month after the end of the chemotherapy, thepatient suffered a sudden reactivation of the pathology, as evidenced bythe radical change of the biological state of the patient. Classicalbiology shows an increase of LDH (347 to 438), alkaline phosphatases (37to 243), SGOT (36 to 84) and SGPT (60 to 135) transaminases, as well asgamma GT (38 to 486), all of which indicate a serious issue at liverlevel. The Biological Simulation Model of example embodiments of thepresent invention shows an outburst of the pathology, as supported bythe evolution of a number of indexes that confirm the generalizedspreading of cancer. These supporting indexes include a relativeincrease of catabolic activity by a factor 10 (0.4 to 4.2); a boost ofGH activity by a factor 16 (2 to 32); an increase in turnover by afactor of 10, favoring the development of malignous cells (11 to 205),associated with a collapse of apoptosis by a factor of 80 (2.46 to0.03); a collapse of anti-growth factors by a factor of 40 (somatostatin16.9 to 0.4); and a sharp increase of the bone remodeling (3 to 68),coupled with a boost of the estrogens metabolic activity (0.3 to 1.4),which indicates the development of bone metastases as later confirmed inthe April 12 MRI.

On Apr. 10, 2020, the biological assessment, four weeks later, shows anoutburst of the pathology and a sharp evolution within one month,raising fears of imminent death of the patient. Classical data ofdigestive markers shows the importance of hepatic damage: LDH is sharplyup (438 to 787), as is Alkaline Phosphatases (243 to 860), SGOT (84 to164) and SGPT (135 to 335) transaminases, gamma GT (486 to 1273) and CEA(3.5 to 13.3), with a decrease of osteocalcin blood content (7 to 3),associated with the raise of bone remodeling and metastases. TheBiological Simulation Model of example embodiments of the presentinvention confirms the sharp degradation of the pathology and its linkswith hormonal dysfunctions. In this regard, the Biological SimulationModel shows an increase of the relative catabolic activity (4.2 to 9.8),and an upsurge of GH activity (32 to 229) and bone remodeling,reflecting the spreading of bone metastases. The Biological SimulationModel also shows a strong reactivation of the thyroidian activity (3.8to 15.7), triggered by the upsurge of the beta sympathetic activity(bMSH/aMSH 4.8 to 21.3), and generating a collapse of the parathormoneactivity (4 to 0.6). Finally, the outburst of the estrogens metabolicactivity (1.4 to 4.8) indicates a large use of the last resources of thepatient, coupled with a lack of anti-growth capability (somatostatin 0.4to 0.3). All of these elements give a possible explanation of why thepathology escapes the traditional cancer therapies.

The analysis of this case shows the reliability of the information givenby the Biological Simulation Model indexes, confirmed by the correlationwith the information given by classical biological and radiological data(e.g., CT scan, MRI, PET scan). The multiplicity of dysfunction factorshighlighted in this case raises the need of complementary therapies ablenot only to act on the pathology, but also to contain/correct suchdysfunctions which encourage cancer spreading. The Biological SimulationModel of example embodiments of the present invention may thereforecomplement the classical biology measurements and permit one tounderstand the biological mechanisms underlying a pathology in action.This could open new therapeutic perspectives in the etiologic diagnosticof a pathology, as well as in the tracking of the evolution of the stateof a patient and of the effects of ongoing treatments.

Example Case 13 Evolution of a Metastasized Prostate Cancer

The above sixth example case draws a link between the bone remodelingindex and bone metastasis. Now, a thirteenth example case addresses themajor indexes associated with the overall pathology (metastasizedprostate cancer), and does so based on the sixty-four-year-old patientfrom the sixth example case. Consider the below table in which fivegroups of indexes have been selected for analysis. These five groups ofindexes describe the evolution of the pathology and its degree ofseverity (death occurred two months after the last biology).

Male Norms Index 2007 2007 2007 Mini Maxi Jan. 3 May 9 Oct. 15 Cortisol24 136 8173 3 7 Adaptation 0.33 0.09 0.01 0.25 0.5 (Eosinophils %) 4.01.0 0.5 1.0 5.0 Serotonin 264 93 49900 1.5 7.5 GH 62 21 83 2 6 GrowthIndex 1567 23650 506730 40 1000 Bone Remodeling 62 25 80 2.5 8.5Adenosis 10⁵ 10⁵ 3302 10 30 Anti-Growth 1.0 8.4 0.7 10 15 Somatostatin0.04 0.06 9 × 10⁻⁵ 1.5 5 Necrosis 521 12 417 2.5 6 Inflammation 1695 5828384 0.3 2.5 Apoptosis Rate  10⁻⁴   10⁻³   10⁻⁴ 0.3 0.7 Fibrosis Rate1.1 5.0   10⁻³ 6 8 Insulin 13.6 6.0 153 1.5 5 Insulin Resistance  10⁻³0.01   10⁻⁷ 0.8 1.3 Oxidoreduction  10⁶   23    10¹¹ 0.7   10¹¹βMSH/αMSH 4.9 7.0 16.5 6 8 Thyroid Yield 3.7 6.1 24 1.5 2.5 CancerExpansivity 1408 236 1806 0.01 3.2

The first group of indexes, including the cortisol, adaptation,eosinophils (percentage) and serotonin indexes, indicates the importanceof the aggression and the huge resources provided by the adrenal gland(cortisol). The adaptation ratio accordingly reduces sharply illustratedby the eosinophils content of the leucocytes (0.1%).

The second group of indexes includes the GH, growth, bone remodeling,adenosis, anti-growth and somatostatin indexes. As to these indexes,cancer is a degenerative pathology with unlimited proliferation ofmalignant cells, requiring an upsurge of growth hormone activity (GH),with a sharp reduction of the anti-growth activity (includingsomatostatin) and an hyperplasic growth illustrated by the adenosisindex.

The third group of indexes includes the necrosis, inflammation,apoptosis and fibrosis indexes. As to this third group, differentcellular deaths are deeply perturbed by the pathology with a sharpreduction of apoptosis (0.0001), a surge of necrosis (416) linked with avery high inflammation and a fibrosis, initially high and collapsing(0.004) when the organism cannot any more fence the impacted area.

The fourth group of indexes includes the insulin, insulin resistance,oxidoreduction, βMSH/αMSH and thyroid yield indexes. These indexesillustrate the disorders created by the huge energy needs for theproliferation of malignant cells, in terms of insulin upsurge, withsharp reduction of insulin resistance to let the glucose access themalignant cells, the associated growth of oxidoreduction and freeredicals, and an upsurge of the thyroid (3.7 to 24), triggered by asharp increase of the betasympathetic (beta/alpha balance measured bythe βMSH/αMSH index), to organize the energy distribution.

The fifth group includes one index, cancer expansivity, whichillustrates the generalized proliferation of the pathology.

4-3. Testing the Biological Simulation Model on the Endocrine System

Consider the graph of the endocrine system shown in FIG. 7.

The functioning of the global metabolism of the human organism impliesthat the endocrine system acts along a precise sequence of catabolic andanabolic alternate phases, which repeats indefinitely.

This sequence starts from the corticotrope axis, moves to gonadotropeaxis, then to thyrotrope axis and somatotrope axis, to restartindefinitely from the corticotrope axis along the same scenario, in linkwith the regular “vertical” activity of each of these axes, workingalong a similar feedback system.

The EMA™ system gives a way to evaluate the internal endocrine systemrelationships along vertical, horizontal and radial links.

A. The corticotropic axis plays a critical role in the energydistribution. It is the starting point of the General AdaptationSyndrome, which represents the response of the organism to internal orexternal aggressions. It has also a so-called permissive role in thesecretion activation of other endocrine axis.

The metabolic activity of the corticotropic axis is primarily catabolic.It covers the protide metabolism (increased catabolism of muscular,osseous, cutaneous, adipic and lymphoid tissues), the carbohydratesmetabolism (increases glycemia by increasing gluconeogenesis andinsulinic resistance), the lipid metabolism (by decreasing the hepaticlipogenesis, and increasing Free Fatty Acids), and the hydroelectricmetabolism (reduces intracell water penetration and facilitates Na+re-absorption and K+ urinary elimination).

The physiological activity of the corticotropic axis relates tointeraction with the cardiovascular system (amplifies vasoconstrictingimpact of catecholamines, such as adrenalin, increase sinoatrialconduction), the digestive system (increases lymphatic absorption ofinsoluble fats, increases gastric hyperchlorhydria), the circulatorysystem (increases content of neutrophils, red cells and platelets bysplanchnic liberation, reduces blood content of eosinophils bysequestration in lungs or in spleen), and the nervous system (amplifiesalpha sympathetic activity and reduces pituitary responses tohypothalamus hormones).

Under therapeutic influence, it amplifies anti-inflammatory andanti-allergic actions.

B. The gonadotropic axis manages the overall sexual hormones, which playa critical role on anabolism, particularly for the protein anabolism,the muscular development and the skeletal maturation.

The metabolic activity of the gonadotropic axis is strongly anabolic,with direct access on the cell nucleus. This includes, for estrogens,preparation and production of anabolism building blocks; for androgens,organization and completion of anabolism (architecture). It includes,for progesterone, intermediate role between estrogens and androgens,extend action of estrogens, delay action of androgens, bothanti-estrogens and anti-androgens activities. And it includes, foradrenal androgens, lower secretion level than genital androgens,important role in 3 periods in life: puberty period (initiation ofgenital function), end of pregnancy (preparation of childbirth) andandropause/menopause (buffering genital secretion deficiencies).

As to the physiological activity of the gonadotropic axis, forestrogens, its predominant role is on osseous structure, stimulatinggrowth of bone and bone cartilage. For androgens, its predominant roleis on musculature, stimulating pineal growth (stature), close theepiphyseal cartilage (end of growth). And for adrenal androgens, itplays a minor role, except during puberty (construction role) and duringgenital pause (moderating catabolic effects of glucocorticoids).

C. The thyreotropic axis mobilizes the energy reserves of the organismby increasing the basic metabolism, and acts upon the somatotrope axisto initiate the reconstruction phase. The role of the thyroid is tosupport catabolism, in order to bring to all levels of the organism thenecessary materials required for the anabolic reconstruction. At bonelevel, the thyroid initiates the bone to liberate the calcium in orderto facilitate reconstruction activity.

The metabolic activity of the thyreotropic axis is strongly catabolic.It increases cell oxygen uptake, generating a catabolism of energeticsubstrates and an increase of metabolism. It also increases glycemia bystimulating gluconeogenesis and glucogenesis, and increases lypolisis ofadipic tissue and increases blood content of Free Fatty Acids, capturedby muscles. Further, it balances proteinic anabolism and catabolism ineuthyroidism state.

The physiological activity of the thyreotropic axis has an impact on thenervous system (supports neuronal development from second trimester offoetus life through early post-natal life, helps maintain normaloxidative status in the brain, preventing neurologic degenerativedisorders). It also has an impact on growth and development (stimulatesgrowth factors and increases number of glucose receptors during periodof increased metabolic demand, increases angiogenesis). And it has animpact on the musculoskeletal system (increases osteoclasy for bonerebuilding, and muscle tone and development), and cardiac system(permissive effect on catecholamines for improving cardiac conductionand myocardial contractility).

More particularly, TRH alters rate and accuracy of DNA transcription,favors a pro-inflammatory state in a terrain with estrogen relaunchingof thyroid axis and an hyper catabolic state, and stimulates endocrinepancreas for insulin release as well as through its stimulation ofprolactin. And TSH increases insulin resistance, stimulates endocrinepancreas, increases cell turnover and membrane stability, increases rateof fibrosis.

D. The somatotrope axis is the constructor of the body. It has a strongdependence on the thyreotropic axis at every level (TRH, TSH and thyroidhormones) creating a fifth virtual “thyreo-somatotropic” axis. It servesat the end of the adaptation cycle for doing the reconstruction work torestore the initial state of the body.

The metabolic activity of the somatotrope axis is strongly anabolic,having a number of hormones involved in energy substrates. And in termsof acquisition and utilization, it ensures through growth andanti-growth factors the level of nutrient utilization and the cohesionof its integration.

More particularly, glucagon is stimulated by adrenaline and TRH, plays arole in short term energy management via glycogenolysis in the liver andlong term glucose management via neoglucogenesis, and competes withinsulin to control glycemia. Insulin resistance is not an hormone, but astate that blocks insulin's metabolic activity to time nutrient entry tocell growth cycle, stimulated by low TSH, low prolactin and high GH andconversely inhibited by the reverse. Insulin supports production andstorage of all energy elements (proteins by stimulating their synthesis,fats by inhibiting glycolysis and stimulating lipogenesis, glucose byinhibiting glycolysis and supporting neoglucogenesis). It can act as agrowth factor if it follows GH (distribution of nutrients) or as ananti-growth factor, if it precedes GH (pathological situation).

The physiological activity of the somatotrope axis provides (viaglucagon) and dispenses (via insulin) a brief and intense energy(glucose) to maintain the basal metabolic activity and ensure sufficientadaptation (glucose oxidation).

More particularly, GH is inhibited by somatostatin and accelerates therate of protein synthesis for cell development and, upon initiation ofthe General Adaptation Syndrome and the thyreotropic axis, helpsreconstruction to restore the initial state, once catabolism has beenestablished (corticotropic and thyreotropic axis), and acts ongonadotropic axis to rebuild its reserves of raw materials. prolactin isintermediate between growth and anti-growth, reduces GH (but GH does notstimulate prolactin), is reduced by dopamine and estrogens, interruptssomatotropic cycle to relaunch ACTH and corticotropic axis, isstimulated directly by TRH which influences the passage from FSH to LHfor androgen production, and can stimulate alpha sympathetic when inpermanent increase. And Insulin distributes glucose to cells or sends itto liver for reserves, its synthesis is stimulated by hyperglycemia, isinhibited by somatostatin, Alpha sympathetic and a high TSH, and canblock GH if hyperinsulinemia.

In summary and with reference to FIG. 8, the metabolism of the body isdivided into two categories complementary and tightly interlinked:

a. catabolism: an activity of destruction, breaking down of substancesand creation of energetic elements, and

b. anabolic: an activity of reconstruction, building up of substancesand utilization of energetic elements.

There cannot be any anabolism without a catabolism phase, and viceversa. The endocrine system follows that logic, and it is imperative tostudy closely the link between the axes to get a complete picture of theorganism.

More information regarding application of the Biological SimulationModel according to the endocrine system according to exampleembodiments, see the attached Evaluation Guidelines.

4-4. The Endobiogenic Medical Assistant (EMA™)

Referring to FIG. 9, a block diagram of one type of apparatus configuredaccording to exemplary embodiments of the present invention is provided,such as an apparatus configured to function as an EMA™. The apparatusincludes various means for performing one or more functions inaccordance with exemplary embodiments of the present invention,including those more particularly shown and described herein. It shouldbe understood, however, that one or more of the entities may includealternative means for performing one or more like functions, withoutdeparting from the spirit and scope of the present invention.

Generally, the apparatus of exemplary embodiments of the presentinvention may comprise, include or be embodied in one or more fixedelectronic devices, such as one or more of a laptop computer, desktopcomputer, workstation computer, server computer or the like.Additionally or alternatively, the apparatus may comprise, include or beembodied in one or more portable electronic devices, such as one or moreof a mobile telephone, portable digital assistant (PDA), pager or thelike.

As shown in FIG. 9, the apparatus 10 of one exemplary embodiment of thepresent invention may include a processor 12 connected to a memory 14.The memory can comprise volatile and/or non-volatile memory, andtypically stores content, data or the like. In this regard, the memorymay store content transmitted from, and/or received by, the apparatus.The memory may also store one or more software applications 16,instructions or the like for the processor to perform steps associatedwith operation of the apparatus in accordance with exemplary embodimentsof the present invention (although any one or more of these steps may beimplemented in hardware alone or in any combination with software and/orfirmware).

In addition to the memory 14, the processor 12 may also be connected toat least one interface or other means for displaying, transmittingand/or receiving data, content or the like. In this regard, theinterface(s) may include at least one communication interface 18 orother means for transmitting and/or receiving data, content or the like,such as to and/or from other device(s) and/or network(s) coupled to theapparatus. In addition to the communication interface(s), theinterface(s) may also include at least one user interface that mayinclude one or more wireline and/or wireless (e.g., Bluetooth) earphonesand/or speakers, a display 20, and/or a user input interface 22. Theuser input interface, in turn, may comprise any of a number of wirelineand/or wireless devices allowing the entity to receive data from a user,such as a keyboard or keypad, a joystick, or other input device.

The EMA™ according to one exemplary embodiment may be implemented as aweb-accessible system in which the apparatus 10 may function as a webserver receiving information from and providing information to users ofsimilar apparatuses that may function as clients.

In accordance with exemplary embodiments, the EMA™ assists apractitioner across the whole patient process to get the best possibleevaluation of the state of the patient and create the relevantprescription. FIG. 10 illustrates an overall system flow according tovarious exemplary embodiments. As shown, the system flow may besummarized through five phases:

1. patient antecedents (for new patient) followed by add-consultation(all patients);

2. clinical examination and conclusions on clinical diagnostic;

3. physiological examination and conclusions on physiologicaldiagnostic;

4. selection of axial and symptomatic actions; and

5. selection of therapeutic items and creation of prescription.

The clinical examination phase may follow the classical approach withidentification of subjective (patient based) signs and objective signs(result of clinical review). The diagnostic will lead to a set ofsymptomatic actions to select from a pre-defined list of 32 items oradd, if required.

The physiological examination phase takes, as its source of data, theBiological Simulation Model defined from the blood test data, includinga set of indexes to be analyzed by endocrine axis. The objective is toidentify the list of endocrine dysfunctions underlying the state of thepatient and requiring corrective actions. In total, there are 43possible actions, of which many are mutually exclusive, for example,inhibit versus trigger a hormone or an organ. In practical terms ananalysis of the endocrine system will generate between six and twelvecorrective actions, depending on the severity of the dysfunctions. Thesystem recommends a set of actions for the practitioner to select and/oradd, if required.

In the therapeutic phase, EMA™ recommends a set of therapeutics for boththe axial and the symptomatic actions for the practitioner to selectand/or add and based on the user input, it produces a full prescription,including dosage.

Reference is now made to FIGS. 11-36, which illustrate portions ofvarious example displays that may be presented by EMA™ during operation.As shown in FIGS. 11 and 12, a user accessing EMA™ may be presented witha display including information regarding EMA™, and a display from whicha user may authenticate or otherwise login to the system. After loggingin to the system, the user may be presented with a home page such asthat shown in FIG. 13. The home page includes a number of links foraccessing features of the system, and for which the user may obtaininformation by selecting the “Quick Start Guide” link. As also shown inthe home page, under “General Tools,” the user may change informationspecific to their account (such as username and password). Under“Reports,” the user may view security activity concerning their accountand the full history of patient data. Under “Data Collection Tools,” theuser may manage Patient data, and under “Core Data Tools,” the user maymanage patient basic information and their own security profile.

Also under “Data Collection Tools,” the home page includes an “AddConsultation Wizard” to access a wizard for guiding the user throughentering patient data and creating a new consultation. In this regard,selecting the “Add Consultation Wizard” may direct the user to an addconsultation screen such as that shown in FIG. 14. From the wizardscreen, the user may select an existing patient, or if the desiredpatient does not exist within the system, add a new patient. Ininstances in which a new patient is being added, the user may select“add patient” to direct the system to present an add-patient display,such as that shown in FIG. 15, from which the user may enter patientadministrative data into the system (including a patient picture ifdesired), and then return to the add consultation screen.

A user may select an existing or newly-added patient from the wizardscreen by selecting the “Add New Consultation” beside the respectivepatient's name. The system may respond by presenting the first of anumber of displays of the consultation wizard, namely the consultationinformation display, such as that shown in FIG. 16. From this display,the user may select the doctor, facility, date of treatment, whether thepatient has cancer, and notes about the consultation.

From the consultation information display, the user may also access apatient review, such as that shown in FIG. 17, from which the user mayedit patient basic information and patient history for an existingpatient or enter patient history for a new patient. For example, asshown in FIG. 18, patient antecedents may be added or edited byselecting “Add New Patient Antecedent Items,” and selecting theappropriate classification (four possibilities: From Conception toChildbirth, Medical Antecedents, Risk factors and Lifestyle habits, Listof Vaccinations). Once the user has selected the classification, theuser will be offered a two-level menu of possible antecedents to choosefrom:

EXAMPLE

If a triangle is presented on the first menu, it indicates asub-classification to address specific diseases, e.g., Diabetes withinEndocrine, Hepatitis within Digestive, or a differentiation between Menand Women for Genital Diseases.

Once the user has selected all Antecedents, the user may enter a datefor occurrence of each Antecedent and enter by selecting “Add SelectedItems to Patient Antecedents,” as shown in FIG. 19. The user may alsoadd summary notes to different categories to be included in the patientsfile or add additional details to the antecedents you selected, as shownmore particularly in FIG. 20.

After entering the patient antecedents, the EMA™ (the system) maypresent a patient examination display, an example of which is shown inFIG. 21. As shown in FIG. 21, the patient examination display mayinclude (shown at the bottom of the display), a drop-down menu thatenables the user to enter Subjective Signs, Measurements, ObjectiveSigns and Newly Diagnosed Medical Antecedents. And as shown moreparticularly in FIG. 22, the display may also include a number of othersections including a Patient Examination Summary (notes from the user),Subjective Signs (as indicated by the Patient), an Objective Signssection for receiving information regarding the respective signsidentified during the clinical examination, and a Newly DiagnosedMedical Antecedents section (notes only), the actual antecedents areselected in the lower section. The other sections may further include aMeasurements section that may receive from the user, the basicmeasurements taken during the consultation, or taken by an assistant(blood pressure, height, weight, and pulse). In this regard, thepatient's body-mass index (BMI) may be automatically computed.

After completing the patient examination display, the user may proceedto the next display of the consultation wizard, namely theconsultation-type display, an example of which is shown in FIG. 23. Fromthis display, the user may decide how they wish to proceed in thewizard. As shown, the two principal options are an index-basedconsultation (leading to the biology of functions) with a consultationusing generated indexes from lab work data, or a symptomaticconsultation with a consultation based on the symptoms identified duringthe Clinical Examination, without lab work data. In an instance in whichlab work is available and has been entered in a lab test manager, theuser may select “Edit Recent Lab Work.” In this regard, the lab testmanager may be implemented in separate software that enables the user toenter lab test when received, independent of a consultation. The datamay then be recalled at the time of a consultation. On the other hand,in an instance in which lab work has not yet been entered, the user maymanually enter the lab work data by selecting “Manually Enter/Import LabWork” and entered either manually or by uploading an Excel spreadsheet.

In an instance in which the user selects the symptomatic consultationoption, the user may be directed to an action-summary selection displaythat in this instance, may present an entire menu of possible actions(axial or symptomatic) without recommendations. The user may then selectfrom those actions based on their patient interview and clinicalexamination. An example of this display is shown in FIG. 32.

In an instance in which the user selects an “Index Based Consultation,”the user may first enter the lab data into the system, such as byselecting “Manually Enter/Import Lab Work” to open an add-lab-testdisplay such as that shown in FIG. 24. From this display, the user mayenter information on: patient name, blood index category (male or femalefor adults or for children), and pregnancy or cancer state of thepatient. The user may also enter information on the date of the lab test(anterior to the date of the consultation), which will sort out thesequencing of the biologies in a consolidated biology report. If thedate is left blank, the system may default this date to the date of theconsultation. Further, the user may enter the dates of last menstruationand chemotherapy, both factors that may distort some indexes or somedata from the test (Leucocytes, e.g., for chemotherapy). The lab testdate has to be set up prior to the chemotherapy date. And the user mayenter the name of the testing lab, such as for further understanding oflab norms needed for four basic data (LDH, CPK, Osteocalcin and Alkalinephosphatases). The user may then select “Next” to manually enter the labresults, or select “Import Lab Results” to import the lab results (e.g.,from the lab, or from a central facility within a hospital, clinic orresearch group).

In an instance in which the user chooses to manually enter the labresults, the add-lab-test display may further present a “Lab Test/BloodWork Index Results” section, as shown for example in FIG. 25. From thissection, the user may start with the four lab norms (mini-maxi) for LDH,CPK, Osteocalcin and Alkaline phosphatases. In this regard, the sum ofthe leucocytes % distribution should add to 100%, as should the sum ofthe Isoenzymes % distribution. The system may be configured to acceptany sum between 99 and 101% for these values, and may show a red flag ifthe sum is under/above this band. Also of note, the data needed for theBiological Simulation Model start with the red cells data and finishwith the calcium data. Other data may be required and are optional, andthe list may be extended to cover multiple uses.

After entering the lab results, the user may select “Next” to direct thesystem to present a biology-of-function report display, such as thatshown in FIG. 26. This display includes indexes of the BiologicalSimulation Model regrouped along the four endocrine axes and along aspecial grouping related to carcinogenesis relevant indexes. Thisdisplay may also repeat the lab results at the end of the biology. In aninstance in which there has been a previous biology entered for thepatient, the last one preceding the current biology will be shownautomatically to highlight comparisons between the last two biologies.For the biologies, the report display may provide a color or otherindication of whether an index is above, below or within norms. Thereport display may also provide an arrow or other indication of whetherthe current biology is up or down versus the last biology, and mayfurther provide emphasis in instances in which the current biology isstrongly up or down.

As also shown, each index has two numbers labeled “s” and “f.” In thisregard, “f” refers to function and provides a measure of the activity ofa hormone or an organ in a given environment. And “s” refers tostructure and provides a measure of the same activity, but excluding theimpact of the adaptation. The structure and display values may bepresented in a number of different manners. For example, the values maybe stacked one below the other, or may be split in different columns.Many indexes have the same value for structure and function, which meansthat the adaptation impact is negligible for those particular indexes.Other indexes may have significantly different values for structure andfunction, e.g., a highly stressed person may have different values forcortisol, adrenal gland, metabolism rate, insulin or the like.

Various ones of the indexes may be visualized on a graph for trend andcomparison purposes, and may be selected for visualization by acheck-box or other means. The same facility may also exist on afull-biology-of-functions report display, which may permit the user tohighlight on a graph the full history of an index.

Generally, the system provides two graphic options. In a first option,as shown for example in FIG. 27, a trend graph may be presented. Thetrend graph may be presented on a normal or logarithmic scale. In asecond option, as shown for example in FIG. 28, a norms graph may bepresented. This graph highlights the indexes selected in comparison withnorms. The technique used is the variance to mid point of the norms, tobe able to put different norms on a same graph. Both graphs may coverthe entire biologies entered in the system.

Returning to the biology-of-function report display, the user maycontinue by selecting “Next” to begin a biological analysis of thepatient by axis: corticotrope, gonadotrope, thyrotrope and somatotrope.There are forty-two possible axial actions over the endocrine system,including two actions not covered by the system (stimulate or inhibitparasympathetic) that can only be identified from the clinicalexamination. The system will recommend actions by axis, but the userdoes not have to make a selection for each axis as all recommendedactions are recapped at the end, in an action module of the wizard.Notably, the consistency and the repeatability of the BiologicalSimulation Model are ensured by the interlink between different indexes:84% of the indexes are indirect, i.e., indexes of indexes, because thisis the way the organism works. Accordingly, everything is interlinked,and the system takes this into account in the algorithm built to produceaxial recommendations.

Examples of the biological analyses displays for the corticotrope andgonadotrope axes are shown in FIGS. 29 and 30, respectively. Thesedisplays may include a notes section intended to carry the user'spersonal observations as the user goes through each axis, which notesmay then reappear in a biology summary display, where the user may wishto make their overall synthesis for the patient report. Also, as shownin FIG. 30, as the user moves their on-screen cursor over an index, thesystem may present a definition of the index.

In addition to the four axes, the biological analysis of the patient mayalso cover a fifth element, which is not an axis analysis. Instead, thefifth element shows indexes specially designed to track a degenerativeprocess such as the cancer disease. Like any index, one generally cannotmay any conclusions from a single index value, but instead from a seriesof indexes that can picture the overall parameters playing a role in thedisease. If some indexes like DNA fracture, cell fracture, globalexpansiveness can give some indications, global factors such as thestrength of activity of the immune system, the Growth Hormone, theestrogens, the anti-growth factors, the thyroid, the oxidoreduction, mayplay equally a major role in the evolution of the disease.

As shown in FIG. 31, for example, the system may display a biologysummary report after the user navigates through the axes. It shows thekey indexes for the current biology with the same code of evolution fromthe previous biology (circles for position versus norms, before and now,and an arrow indicating the trend). A space may be reserved for thepersonal conclusions of the user on the biology axial analysis.

FIG. 32 illustrates an example action summary selection display, whichmay be next presented in the process. This display includes threecolumns. In one column, the display includes a recap of the recommendedaxial actions. In another column, the display includes the set of otherpossible axial actions. And in the third column, the display includesthe set of possible symptomatic actions.

From the action summary selection display, the user may select some orall of the recommended actions and/or select some of the complementarylist of axial actions, as well as select some of the symptomaticactions, if needed, for complementary actions. In an instance in whichthe user does not have a biology for the patient, the user may selectsome of the symptomatic actions. The user may also select some of theaxial actions if their clinical examination could identify someendocrine dysfunctions suggesting some specific axial actions, withoutsystem recommendations. Notably, the system may not trigger two axialactions (stimulate or inhibit para sympathetic) as they are expected tobe selected upon the outcome of the clinical examination, if required.

As another step in the process, the system may present a treatment plandisplay, such as that shown in FIG. 33. Here the user may selectmedications (selected items highlighted) to be included in a treatmentplan, for both axial and symptomatic actions. Generally, a single choiceis offered by action. A multiple choice may be offered to provide analternative choice, in case of conflicting effects of product propertieswith the patient configuration.

The system may also present a prescription display such as that shown inFIG. 34. This display may summarize the physiological actions selectedand the associated medications automatically combined into custompreparations, where possible, with dosage. The system may also provideprice quotes and prescription assistance, such as by the user selecting“Prescription assistance,” and an order may be requested directly from aselected medication provider.

Finally, the system may present a doctor report display, such as thatshown in FIG. 35. The report provided by this display may be reviewed bythe user, and may be sent from the user to another user such as to acolleague practitioner. The system provides two variations of thereport, namely a patient report and a prescription report.

According to one aspect of the present invention, all or a portion ofthe apparatus of exemplary embodiments of the present invention,generally operates under control of a computer program. The computerprogram for performing the methods of exemplary embodiments of thepresent invention may include one or more computer-readable program codeportions, such as a series of computer instructions, embodied orotherwise stored in a computer-readable storage medium, such as thenon-volatile storage medium.

It will be understood that each step of a method according to exemplaryembodiments of the present invention, and combinations of steps in themethod, may be implemented by computer program instructions. Thesecomputer program instructions may be loaded onto a computer or otherprogrammable apparatus to produce a machine, such that the instructionswhich execute on the computer or other programmable apparatus createmeans for implementing the functions specified in the step(s) of themethod. These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable apparatus to function in a particular manner, such that theinstructions stored in the computer-readable memory produce an articleof manufacture including instruction means which implement steps of themethod. The computer program instructions may also be loaded onto acomputer or other programmable apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing steps of the method.

Accordingly, exemplary embodiments of the present invention supportcombinations of means for performing the specified functions,combinations of steps for performing the specified functions and programinstruction means for performing the specified functions. It will alsobe understood that each step or function, and combinations of steps orfunctions, can be implemented by special purpose hardware-based computersystems which perform the specified functions or steps, or combinationsof special purpose hardware and computer instructions.

4-5. Conclusions

The methodology of example embodiments of the present invention is basedon the current knowledge of the Physiological science: it provides anintegrative new way of assessing the functioning of the organism, whichpositions the endocrine systems as the manager of theendocrino-metabolic and tissular equilibrium of the human body.

Using biological data obtained from a simple blood analysis, it permits,through a new approach on the linkage between the endocrine systemelements (axis), to assess the functionality of these elements at cell,tissue, and global level.

The benefits of this approach are multiple:

1. assistance for a quantified evaluation of the functional biologicalstate of a patient; identification of physiological dysfunctions linkedwith diseases; proposition of diagnostic conclusions;

2. assistance for selecting therapeutic treatment;

3. assistance for tracking efficiency of therapeutic treatments:modifications induced on the physiological state of the patient; earlybiological detection of drug side effects before clinical evidence;

4. assistance for prevention: early detection of pathology risks; and

5. assistance for research work: new links between physiologicalimbalances and specific diseases.

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing descriptions andthe associated drawings. It should therefore be understood that theinvention is not to be limited to the specific embodiments disclosed andthat modifications and other embodiments are intended to be includedwithin the scope of the appended claims. Although specific terms areemployed herein, they are used in a generic and descriptive sense onlyand not for purposes of limitation.

What is claimed is:
 1. A method comprising: receiving measurements ofbiological elements from a blood sample of a patient, the respectivebiological elements being managed by hormones produced by glands of theendocrine system of the patient, wherein the glands and respectivehormones are organizable in axes including a corticotropic axis,gonadotropic axis, thyreotropic axis and somatotropic axis; calculatinga plurality of indexes as functions of the measurements, reflectingphysiological relationships between the biological elements and thehormones that manage the respective biological elements, at least someof the indexes reflecting physiological relationships between hormonesacross axes of the endocrine system; evaluating the indexes by axis ofthe endocrine system and in sequence from the corticotropic axis to thegonadotropic axis, and then to the thyreotropic axis and somatotropicaxis, the indexes being evaluated to facilitate identification of one ormore dysfunctions capable of participating in the genesis, installationand evolution of a pathology, and thereby identify a functionalimbalance in a state of the patient; and generating a recommendedtherapeutic strategy for the patient to facilitate correction of theidentified functional imbalance.
 2. The method of claim 1, whereinreceiving the measurements, calculating the plurality of indexes andevaluating the indexes occur in a first instance to identify thefunctional imbalance, and occur in a second instance subsequent to anadministering of the recommended therapeutic strategy to therebyvalidate the identified functional imbalance and efficiency of therecommended therapeutic strategy.
 3. The method of claim 1, whereinreceiving the measurements includes receiving the measurements to anapparatus including a processor and a memory storing executableinstructions that in response to execution by the processor cause theapparatus to at least calculate the plurality of indexes.
 4. The methodof claim 1, wherein calculating the plurality of indexes includescalculating one or more direct indexes as functions of variablesincluding the measurements, and calculating one or more indirect indexesas functions of variables including the one or more direct indexes. 5.The method of claim 4, wherein each of one or more indexes evaluate alevel of activity, yield or circulating rate, and include as variables,measurements or direct indexes affecting the respective level ofactivity, yield or circulating rate.
 6. The method of claim 5, whereinat least one of the respective one or more indexes is in the form of aratio including a numerator and denominator, and include a variable inthe numerator to reflect the level of activity, yield or circulatingrate varying like the respective variable, or a variable in thedenominator to reflect the level of activity, yield or circulating ratevarying like the reverse of the respective variable.
 7. The method ofclaim 1 further comprising: administering the recommended therapeuticstrategy to the patient.
 8. The method of claim 1, wherein evaluatingthe indexes includes for each axis of the endocrine system, evaluating asubset of the indexes according to a predetermined search sequence ofthe indexes of the respective subset.
 9. A method comprising: receivingmeasurements of biological elements from a blood sample of a patient,the respective biological elements being managed by hormones produced byglands of the endocrine system of the patient, wherein the glands andrespective hormones are organizable in axes including a corticotropicaxis, gonadotropic axis, thyreotropic axis and somatotropic axis;calculating a plurality of indexes as functions of the measurements,reflecting physiological relationships between the biological elementsand the hormones that manage the respective biological elements, atleast some of the indexes reflecting physiological relationships betweenhormones across axes of the endocrine system; and evaluating the indexesby axis of the endocrine system and in sequence from the corticotropicaxis to the gonadotropic axis, and then to the thyreotropic axis andsomatotropic axis, the indexes being evaluated to facilitateidentification of one or more dysfunctions capable of participating inthe genesis, installation and evolution of a pathology, and therebyidentify a functional imbalance in a state of the patient, whereinevaluating the indexes also facilitate generation of a recommendedtherapeutic strategy for the patient to facilitate correction of theidentified functional imbalance, wherein receiving the measurements,calculating the plurality of indexes and evaluating the indexes areperformed by an apparatus including a processor and a memory storingexecutable instructions that in response to execution by the processorcause the apparatus to at least receive the measurements, calculate theplurality of indexes and evaluate the indexes.
 10. The method of claim9, wherein receiving the measurements, calculating the plurality ofindexes and evaluating the indexes occur in a first instance to identifythe functional imbalance, and occur in a second instance subsequent toan administering of the recommended therapeutic strategy to therebyvalidate the identified functional imbalance and efficiency of therecommended therapeutic strategy.
 11. The method of claim 9, whereincalculating the plurality of indexes includes calculating one or moredirect indexes as functions of variables including the measurements, andcalculating one or more indirect indexes as functions of variablesincluding the one or more direct indexes.
 12. The method of claim 11,wherein each of one or more indexes evaluate a level of activity, yieldor circulating rate, and include as variables, measurements or directindexes affecting the respective level of activity, yield or circulatingrate.
 13. The method of claim 12, wherein at least one of the respectiveone or more indexes is in the form of a ratio including a numerator anddenominator, and include a variable in the numerator to reflect thelevel of activity, yield or circulating rate varying like the respectivevariable, or a variable in the denominator to reflect the level ofactivity, yield or circulating rate varying like the reverse of therespective variable.
 14. The method of claim 9 further comprising:generating the recommended therapeutic strategy for the patient tofacilitate correction of the identified functional imbalance.
 15. Themethod of claim 9, wherein evaluating the indexes includes for each axisof the endocrine system, evaluating a subset of the indexes according toa predetermined search sequence of the indexes of the respective subset.16. An apparatus comprising a processor and a memory storing executableinstructions that in response to execution by the processor cause theapparatus to at least: receive measurements of biological elements froma blood sample of a patient, the respective biological elements beingmanaged by hormones produced by glands of the endocrine system of thepatient, wherein the glands and respective hormones are organizable inaxes including a corticotropic axis, gonadotropic axis, thyreotropicaxis and somatotropic axis; calculate a plurality of indexes asfunctions of the measurements, reflecting physiological relationshipsbetween the biological elements and the hormones that manage therespective biological elements, at least some of the indexes reflectingphysiological relationships between hormones across axes of theendocrine system; and evaluate the indexes by axis of the endocrinesystem and in sequence from the corticotropic axis to the gonadotropicaxis, and then to the thyreotropic axis and somatotropic axis, theindexes being evaluated to facilitate identification of one or moredysfunctions capable of participating in the genesis, installation andevolution of a pathology, and thereby identify a functional imbalance ina state of the patient, wherein evaluating the indexes also facilitategeneration of a recommended therapeutic strategy for the patient tofacilitate correction of the identified functional imbalance.
 17. Theapparatus of claim 16, wherein the apparatus is caused to receive themeasurements, calculate the plurality of indexes and evaluate theindexes in a first instance to identify the functional imbalance, and ina second instance subsequent to an administering of the recommendedtherapeutic strategy to thereby validate the identified functionalimbalance and efficiency of the recommended therapeutic strategy. 18.The apparatus of claim 16, wherein the apparatus being caused tocalculate the plurality of indexes includes being caused to calculateone or more direct indexes as functions of variables including themeasurements, and calculate one or more indirect indexes as functions ofvariables including the one or more direct indexes.
 19. The apparatus ofclaim 18, wherein each of one or more indexes evaluate a level ofactivity, yield or circulating rate, and include as variables,measurements or direct indexes affecting the respective level ofactivity, yield or circulating rate.
 20. The apparatus of claim 19,wherein at least one of the respective one or more indexes is in theform of a ratio including a numerator and denominator, and include avariable in the numerator to reflect the level of activity, yield orcirculating rate varying like the respective variable, or a variable inthe denominator to reflect the level of activity, yield or circulatingrate varying like the reverse of the respective variable.
 21. Theapparatus of claim 16, wherein the memory stores further executableinstructions that in response to execution by the processor cause theapparatus to further: generate the recommended therapeutic strategy forthe patient to facilitate correction of the identified functionalimbalance.
 22. The apparatus of claim 16, wherein the apparatus beingcaused to evaluate the indexes includes for each axis of the endocrinesystem, being caused to evaluate a subset of the indexes according to apredetermined search sequence of the indexes of the respective subset.23. A computer-readable storage medium for performing aperformance-option valuation, the computer-readable storage mediumhaving computer-readable program code portions stored therein that inresponse to execution by a processor cause an apparatus to at least:receive measurements of biological elements from a blood sample of apatient, the respective biological elements being managed by hormonesproduced by glands of the endocrine system of the patient, wherein theglands and respective hormones are organizable in axes including acorticotropic axis, gonadotropic axis, thyreotropic axis andsomatotropic axis; calculate a plurality of indexes as functions of themeasurements, reflecting physiological relationships between thebiological elements and the hormones that manage the respectivebiological elements, at least some of the indexes reflectingphysiological relationships between hormones across axes of theendocrine system; and evaluate the indexes by axis of the endocrinesystem and in sequence from the corticotropic axis to the gonadotropicaxis, and then to the thyreotropic axis and somatotropic axis, theindexes being evaluated to facilitate identification of one or moredysfunctions capable of participating in the genesis, installation andevolution of a pathology, and thereby identify a functional imbalance ina state of the patient, wherein evaluating the indexes also facilitategeneration of a recommended therapeutic strategy for the patient tofacilitate correction of the identified functional imbalance.
 24. Thecomputer-readable storage medium of claim 23, wherein the apparatus iscaused to receive the measurements, calculate the plurality of indexesand evaluate the indexes in a first instance to identify the functionalimbalance, and in a second instance subsequent to an administering ofthe recommended therapeutic strategy to thereby validate the identifiedfunctional imbalance and efficiency of the recommended therapeuticstrategy.
 25. The computer-readable storage medium of claim 23, whereinthe apparatus being caused to calculate the plurality of indexesincludes being caused to calculate one or more direct indexes asfunctions of variables including the measurements, and calculate one ormore indirect indexes as functions of variables including the one ormore direct indexes.
 26. The computer-readable storage medium of claim25, wherein each of one or more indexes evaluate a level of activity,yield or circulating rate, and include as variables, measurements ordirect indexes affecting the respective level of activity, yield orcirculating rate.
 27. The computer-readable storage medium of claim 26,wherein at least one of the respective one or more indexes is in theform of a ratio including a numerator and denominator, and include avariable in the numerator to reflect the level of activity, yield orcirculating rate varying like the respective variable, or a variable inthe denominator to reflect the level of activity, yield or circulatingrate varying like the reverse of the respective variable.
 28. Thecomputer-readable storage medium of claim 23, wherein thecomputer-readable storage medium has further computer-readable programcode portions stored therein that in response to execution by theprocessor cause the apparatus to further: generate the recommendedtherapeutic strategy for the patient to facilitate correction of theidentified functional imbalance.
 29. The computer-readable storagemedium of claim 23, wherein the apparatus being caused to evaluate theindexes includes for each axis of the endocrine system, being caused toevaluate a subset of the indexes according to a predetermined searchsequence of the indexes of the respective subset.